Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains

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The LRP6 ectodomain binds Wnt proteins, as well as Wnt inhibitors such as sclerostin (SOST), which negatively regulates Wnt signaling in osteocytes. Although LRP6 ectodomain 1 …"><meta name="keywords" content="pmid:33097721, PMC7585440, doi:10.1038/s41467-020-19155-4, Research Support, Non-U.S. Gov't, Jinuk Kim, Wonhee Han, Hee-Jung Choi, Adaptor Proteins, Signal Transducing / antagonists & inhibitors*, Adaptor Proteins, Signal Transducing / chemistry, Adaptor Proteins, Signal Transducing / metabolism*, Animals, Binding Sites, Crystallography, X-Ray, Female, HEK293 Cells, Humans, Intercellular Signaling Peptides and Proteins / chemistry, Intercellular Signaling Peptides and Proteins / metabolism, Low Density Lipoprotein Receptor-Related Protein-6 / chemistry, Low Density Lipoprotein Receptor-Related Protein-6 / metabolism*, Models, Molecular, Peptides / metabolism, Protein Binding, Protein Conformation, Transcriptome, Wnt Proteins / metabolism*, Wnt Signaling Pathway / drug effects*, Xenopus laevis / embryology, Xenopus laevis / metabolism, beta Catenin / metabolism, PubMed Abstract, NIH, NLM, NCBI, National Institutes of Health, National Center for Biotechnology Information, National Library of Medicine, MEDLINE"><meta name="robots" content="index,nofollow,noarchive"><meta property="og:title" content="Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains - PubMed"><meta property="og:url" content="https://pubmed.ncbi.nlm.nih.gov/33097721/"><meta property="og:description" content="Low-density lipoprotein receptor-related protein 6 (LRP6) is a coreceptor of the β-catenin-dependent Wnt signaling pathway. The LRP6 ectodomain binds Wnt proteins, as well as Wnt inhibitors such as sclerostin (SOST), which negatively regulates Wnt signaling in osteocytes. Although LRP6 ectodomain 1 …"><meta property="og:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:image:secure_url" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg"><meta property="og:type" content="website"><meta property="og:site_name" content="PubMed"><meta name="twitter:domain" content="pubmed.ncbi.nlm.nih.gov"><meta name="twitter:card" content="summary_large_image"><meta name="twitter:title" content="Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains - PubMed"><meta name="twitter:url" content="https://pubmed.ncbi.nlm.nih.gov/33097721/"><meta name="twitter:description" content="Low-density lipoprotein receptor-related protein 6 (LRP6) is a coreceptor of the β-catenin-dependent Wnt signaling pathway. The LRP6 ectodomain binds Wnt proteins, as well as Wnt inhibitors such as sclerostin (SOST), which negatively regulates Wnt signaling in osteocytes. Although LRP6 ectodomain 1 …"><meta name="twitter:image" content="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/pubmed-meta-image-v2.jpg">  <link rel="search" type="application/opensearchdescription+xml" href="https://cdn.ncbi.nlm.nih.gov/pubmed/persistent/opensearch.xml" title="PubMed search">  <noscript> <link rel="stylesheet" type="text/css" href="https://cdn.ncbi.nlm.nih.gov/pubmed/0d576970-ea4f-4f8d-9bab-bf51569c42d2/core/no-script.css"> </noscript> <meta name="citation_title" content="Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains"> <meta name="citation_authors" content="Kim J;Han W;Park T;Kim EJ;Bang I;Lee HS;Jeong Y;Roh K;Kim J;Kim JS;Kang C;Seok C;Han JK;Choi HJ;"> <meta name="citation_date" content="10/23/2020"> <meta name="citation_publisher" content="Nat Commun"> <meta name="citation_journal_title" content="Nature communications"> <meta name="citation_pmid" content="33097721"> <meta name="citation_abstract_html_url" content="https://pubmed.ncbi.nlm.nih.gov/33097721/"> <meta name="citation_volume" content="11"> <meta name="citation_issue" content="1"> <meta name="citation_doi" content="10.1038/s41467-020-19155-4"> <meta name="citation_issn" content="2041-1723"> <link rel="canonical" href="https://pubmed.ncbi.nlm.nih.gov/33097721/" /> </head> <body > <noscript> <div class="no-script-banner" id="no-script-banner"> <div class="warning-message"> <div class="warning-message-text"> This site needs JavaScript to work properly. 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new collection</label> </li> <li> <input type="radio" id="collections-action-panel-existing" class="collections-existing" name="collections" value="existing" checked="true" data-ga-category="save_share" data-ga-action="collections" data-ga-label="collections_radio_existing"> <label for="collections-action-panel-existing">Add to an existing collection</label> </li> </ul> </div> <div class="controls-wrapper"> <div class="action-panel-control-wrap new-collections-controls"> <label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk"> Name your collection: </label> <input type="text" name="add-to-new-collection" id="collections-action-panel-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="100" data-ga-category="save_share" data-ga-action="create_collection" data-ga-label="non_favorties_collection"> <div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div> </div> <div class="action-panel-control-wrap existing-collections-controls"> <label for="collections-action-panel-add-to-existing" class="action-panel-label"> Choose a collection: </label> <select id="collections-action-panel-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="save_share" data-ga-action="select_collection" data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'"> </select> <div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br> <a href="#">Please try again</a> </div> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="save_share" data-ga-action="collections" data-ga-label="add"> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="collections" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="bibliography-action-panel" class="bibliography-action-panel action-panel in-progress-dots-panel" aria-hidden="true" data-bibliography-open-panel-enabled="false" data-bibliography-open-panel-url-hash="#open-bibliography-panel"> <div class="inner-wrap"> <h3 class="action-panel-heading"> Add to My Bibliography </h3> <form id="bibliography-action-panel-form" class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors" data-add-to-bibliography-max-amount="100" data-add-to-bibliography-batch-size="10" data-bibliography-delegates-url="/list-bibliography-delegates/" data-add-to-bibliography-url="/add-to-bibliography/" data-get-article-ids-by-search-url="/get-article-ids-by-search/" data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/"> <input type="hidden" name="csrfmiddlewaretoken" value="xdTdfVGEUMZ5QHuSlQlNXGOnHMmohFIuuyg5ZibeRGAF4FsZpuMP37lEsL1zWdD4"> <div class="action-panel-control-wrap bibliographies-controls"> <div class="choice-group"> <ul class="bibliographies-action-add radio-group-items"> <li> <input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/> <label for="my-bibliography">My Bibliography</label> </li> </ul> </div> </div> <div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your delegates due to an error<br> <a href="#">Please try again</a> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore> Add </button> <button class="action-panel-cancel" aria-label="Close 'Add to bibliography' panel" ref="linksrc=close_bibliography_panel" aria-controls="bibliography-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="mybib" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true" data-saved-search-open-panel-enabled="false" data-saved-search-open-panel-url-hash="#open-saved-search-panel"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your saved search </h2> <form id="saved-search-action-panel-form" class="saved-search-action-panel-form action-panel-content action-form" data-create-saved-search-url="/create-saved-search/" data-try-search-terms-url="/try-search-term/" data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/"> <input type="hidden" name="csrfmiddlewaretoken" value="xdTdfVGEUMZ5QHuSlQlNXGOnHMmohFIuuyg5ZibeRGAF4FsZpuMP37lEsL1zWdD4"> <div class="action-panel-control-wrap"> <label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk"> Name of saved search: </label> <input maxlength="200" type="text" name="saved-search-name" id="saved-search-name" class="saved-search-name" value="" required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="action-panel-control-wrap"> <label for="saved-search-term" class="action-panel-label required-field-asterisk"> Search terms: </label> <textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea> </div> <div class="test-search-term-wrap"> <a href="#" class="try-search-term">Test search terms</a> </div> <div class="choice-group action-panel-extra-margin-top"> <span class="action-panel-label" id="fieldset-label"> Would you like email updates of new search results? </span> <fieldset id="saved-search-alert" aria-describedby="fieldset-label"> <legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend> <ul class="radio-group-items"> <li> <input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked> <label for="saved-search-alert-yes" class="action-panel-label">Yes</label> </li> <li> <input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no"> <label for="saved-search-alert-no" class="action-panel-label">No</label> </li> </ul> </fieldset> </div> <div class="alert-schedule-wrap"> <div class="action-panel-control-wrap"> <label class="action-panel-label"> Email: </label> <span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span> </div> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="saved-search-frequency" class="action-panel-label"> Frequency: </label> <select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency"> <option value="monthly">Monthly</option> <option value="weekly">Weekly</option> <option value="daily">Daily</option> </select> </div> <div class="action-panel-control-wrap saved-search-monthly-additional"> <label for="saved-search-monthly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-monthly-on-day" class="no-border-panel-selector"> <option value="Sunday">The first Sunday</option> <option value="Monday">The first Monday</option> <option value="Tuesday">The first Tuesday</option> <option value="Wednesday">The first Wednesday</option> <option value="Thursday">The first Thursday</option> <option value="Friday">The first Friday</option> <option value="Saturday">The first Saturday</option> <option value="day">The first day</option> <option value="weekday">The first weekday</option> </select> </div> <div class="action-panel-control-wrap saved-search-weekly-additional"> <label for="saved-search-weekly-on-day" class="action-panel-label"> Which day? </label> <select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day"> <option value="Sunday">Sunday</option> <option value="Monday">Monday</option> <option value="Tuesday">Tuesday</option> <option value="Wednesday">Wednesday</option> <option value="Thursday">Thursday</option> <option value="Friday">Friday</option> <option value="Saturday">Saturday</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-report" class="action-panel-label"> Report format: </label> <select id="saved-search-report" class="no-border-panel-selector saved-search-report"> <option value="DocSum">Summary</option> <option value="DocSumText">Summary (text)</option> <option value="Abstract">Abstract</option> <option value="AbstractText">Abstract (text)</option> <option value="MEDLINE">PubMed</option> </select> </div> <div class="action-panel-control-wrap"> <label for="saved-search-amount" class="action-panel-label"> Send at most: </label> <select id="saved-search-amount" class="no-border-panel-selector saved-search-amount"> <option value="1">1 item</option> <option value="5" selected>5 items</option> <option value="10">10 items</option> <option value="20">20 items</option> <option value="50">50 items</option> <option value="100">100 items</option> <option value="200">200 items</option> </select> </div> <div> <input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result"> <label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox"> Send even when there aren't any new results </label> </div> <div class="action-panel-control-wrap option-text-in-email-wrap"> <label for="saved-search-email-text" class="action-panel-label"> Optional text in email: </label> <textarea name="saved-search-email-text" id="saved-search-email-text" class="saved-search-email-text"></textarea> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Saving..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Save </button> <button class="action-panel-cancel" aria-label="Close 'Your saved search' panel" ref="linksrc=close_saved_search_panel" aria-controls="saved-search-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Create a file for external citation management software </h2> <form id="citation-manager-action-panel-form" class="action-panel-content action-form" action="/results-export-ids/" data-by-search-action="/results-export-search-data/" data-by-ids-action="/results-export-ids/" method="post" data-by-search-method="post" data-by-ids-method="post"> <input type="hidden" name="csrfmiddlewaretoken" value="xdTdfVGEUMZ5QHuSlQlNXGOnHMmohFIuuyg5ZibeRGAF4FsZpuMP37lEsL1zWdD4"> <input name="results-format" type="hidden" value="pubmed"/> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Sending..." data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="save"> Create file </button> <button class="action-panel-cancel" aria-label="Close 'Send citations to citation manager' panel" ref="linksrc=close_citation_manager_panel" aria-controls="citation-manager-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="citation_manager" data-ga-label="cancel"> Cancel </button> </div> </form> </div> </div> <div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true"> <div class="inner-wrap"> <h2 class="action-panel-heading"> Your RSS Feed </h2> <form id="rss-action-panel-form" class="rss-action-panel-form action-panel-content action-form" data-create-rss-feed-url="/create-rss-feed-url/" data-search-form-term-value=""> <input type="hidden" name="csrfmiddlewaretoken" value="xdTdfVGEUMZ5QHuSlQlNXGOnHMmohFIuuyg5ZibeRGAF4FsZpuMP37lEsL1zWdD4"> <div class="action-panel-control-wrap"> <label for="rss-name" class="action-panel-label required-field-asterisk"> Name of RSS Feed: </label> <input maxlength="200" placeholder="Name" type="text" name="rss-name" id="rss-name" class="rss-name" value='' required pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/"> </div> <div class="rss-limit-wrap"> <div class="action-panel-control-wrap action-panel-extra-margin-top"> <label for="rss-limit" class="action-panel-label"> Number of items displayed: </label> <select id="rss-limit" class="no-border-panel-selector rss-limit"> <option value="5">5</option> <option value="10">10</option> <option value="15" selected="selected">15</option> <option value="20">20</option> <option value="50">50</option> <option value="100">100</option> </select> </div> </div> <div class="action-panel-actions"> <button class="action-panel-submit" type="submit" data-loading-label="Creating..." data-ga-category="save_share" data-ga-action="alert" data-ga-label="save"> Create RSS </button> <button class="action-panel-cancel" aria-label="Close 'Your RSS' panel" ref="linksrc=close_rss_panel" aria-controls="rss-action-panel" aria-expanded="false" data-ga-category="save_share" data-ga-action="alert" data-ga-label="cancel"> Cancel </button> </div> <div class="action-panel-control-wrap rss-link-copy-wrap"> <label for="rss-link" class="usa-sr-only">RSS Link</label> <input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link"> <button type="button" disabled class="rss-link-copy-button disabled" data-ga-category="save_share" data-ga-action="rss" data-ga-label="copy"> Copy </button> </div> </form> </div> </div> </div> </div> <div class="article-page" id="article-page" data-article-pmid="33097721"> <aside class="page-sidebar"> <div class="inner-wrap"> <div class="full-text-links"> <div class="full-view"> <h3 class="title"> Full text links </h3> <div class="full-text-links-list"> <a class="link-item dialog-focus" 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required-field-asterisk"> Name your collection: </label><input type="text" name="add-to-new-collection" id="collections-action-dialog-add-to-new" class="collections-action-add-to-new" pattern="[^"&=<>\/]*" title="The following characters are not allowed in the Name field: "&=<>/" maxlength="100" data-ga-category="collections_button" data-ga-action="create_collection" data-ga-label="non_favorties_collection"><div class="collections-new-name-too-long usa-input-error-message selection-validation-message"> Name must be less than 100 characters </div></div><div class="action-panel-control-wrap existing-collections-controls"><label for="collections-action-dialog-add-to-existing" class="action-panel-label"> Choose a collection: </label><select id="collections-action-dialog-add-to-existing" class="action-panel-selector collections-action-add-to-existing" data-ga-category="collections_button" data-ga-action="select_collection" data-ga-label="($('.collections-action-add-to-existing').val() === 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'Favorites' : 'non_favorites_collection'"></select><div class="collections-retry-load-on-error usa-input-error-message selection-validation-message"> Unable to load your collection due to an error<br><a href="#">Please try again</a></div></div></div><div class="action-panel-actions"><button class="action-panel-submit" type="submit" data-loading-label="Adding..." data-pinger-ignore data-ga-category="collections_button" data-ga-action="click" data-ga-label="add"> Add </button><button class="action-panel-cancel" aria-label="Close 'Add to Collections' panel" ref="linksrc=close_collections_panel" aria-controls="collections-action-panel" aria-expanded="false" data-ga-category="collections_button" data-ga-action="click" data-ga-label="cancel"> Cancel </button></div></form></div></div></div></div><button class="more-actions-button more-actions-dialog-trigger" title="Open dialog with more actions to take" ref="linksrc=more_actions_btn"></button><div class="display-options" 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class="journal-actions dropdown-block"><button id="full-view-journal-trigger" class="journal-actions-trigger trigger" ref="linksrc=journal_actions_btn" title="Nature communications" tabindex="0" aria-controls="full-view-journal" aria-expanded="false" aria-label="Toggle dropdown menu for journal Nature communications" data-pinger-ignore> Nat Commun </button><div id="full-view-journal" class="journal-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for journal Nature communications"><div class="title">Actions</div><div class="content"><ul class="journal-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Nat+Commun%22%5Bjour%5D&sort=date&sort_order=desc" data-href="/?term=%22Nat+Commun%22%5Bjour%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_journal_name_link&journal_abbrev=Nat Commun" data-ga-category="search" data-ga-action="journal_link" data-ga-label="Nat Commun"> Search in PubMed </a></li><li><a class="search-in-nlm-catalog-link dropdown-block-link" ref ="linksrc=search_in_nlm_catalog_link" href="https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Nat+Commun%22%5BTitle+Abbreviation%5D" data-ga-category="search_catalog" data-ga-action="journal_link" data-ga-label="Nat Commun"> Search in NLM Catalog </a></li><li><a class="add-to-search-link dropdown-block-link" ref ="linksrc=add_to_search_link" role="button" data-search-term='"Nat Commun"[jour]' data-ga-category="search" data-ga-action="add_to_search" data-ga-label='"Nat Commun"[jour]' href="#"> Add to Search </a></li></ul></div></div></div><span class="period">. </span><span class="cit">2020 Oct 23;11(1):5357.</span> </div> <span class="citation-doi"> doi: 10.1038/s41467-020-19155-4. </span> </div> <h1 class="heading-title"> Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains </h1> <div class="inline-authors"> <div class="authors"> <div class="authors-list"> <span class="authors-list-item "><a class="full-name" href="/?term=Kim+J&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Jinuk Kim">Jinuk Kim</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Han+W&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Wonhee Han">Wonhee Han</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, 37673, Republic of Korea." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Park+T&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Taeyong Park">Taeyong Park</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Chemistry, Seoul National University, Seoul, 08826, Republic of Korea." href="#full-view-affiliation-3" ref="linksrc=author_aff"> 3 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Kim+EJ&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Eun Jin Kim">Eun Jin Kim</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Plumbline Life Sciences, Inc., Seoul, 06552, Republic of Korea." href="#full-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Bang+I&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Injin Bang">Injin Bang</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, 10032, USA." href="#full-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Lee+HS&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Hyun Sik Lee">Hyun Sik Lee</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Jeong+Y&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Yejin Jeong">Yejin Jeong</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea." href="#full-view-affiliation-6" ref="linksrc=author_aff"> 6 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Roh+K&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Kyeonghwan Roh">Kyeonghwan Roh</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Kim+J&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Jeesoo Kim">Jeesoo Kim</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Center for RNA Research, Institute for Basic Science, Seoul, 08826, Republic of Korea." href="#full-view-affiliation-7" ref="linksrc=author_aff"> 7 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Kim+JS&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Jong-Seo Kim">Jong-Seo Kim</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Center for RNA Research, Institute for Basic Science, Seoul, 08826, Republic of Korea." href="#full-view-affiliation-7" ref="linksrc=author_aff"> 7 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Kang+C&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Chanhee Kang">Chanhee Kang</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#full-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Seok+C&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Chaok Seok">Chaok Seok</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Chemistry, Seoul National University, Seoul, 08826, Republic of Korea." href="#full-view-affiliation-3" ref="linksrc=author_aff"> 3 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Han+JK&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Jin-Kwan Han">Jin-Kwan Han</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, 37673, Republic of Korea." href="#full-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Choi+HJ&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Hee-Jung Choi">Hee-Jung Choi</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea. choihj@snu.ac.kr." href="#full-view-affiliation-8" ref="linksrc=author_aff"> 8 </a></sup></span> </div> </div> </div> <div class="short-article-details"> Affiliations <button class="more-details" id="toggle-authors" data-alt-text="Collapse" aria-controls="expanded-authors" aria-expanded="false" data-pinger-ignore data-fetch-url="/33097721/long-authors/" data-id-prefix=""> <span class="title"> Expand </span> </button> </div> <div class="extended-article-details" id="expanded-authors" aria-hidden="true"> <div class="expanded-authors" id="full-view-expanded-authors"> <div class="affiliations"> <h3 class="title"> Affiliations </h3> <ul class="item-list"> <li data-affiliation-id="full-view-affiliation-1" id="full-view-affiliation-1" ><sup class="key">1</sup> Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.</li> <li data-affiliation-id="full-view-affiliation-2" id="full-view-affiliation-2" ><sup class="key">2</sup> Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, 37673, Republic of Korea.</li> <li data-affiliation-id="full-view-affiliation-3" id="full-view-affiliation-3" ><sup class="key">3</sup> Department of Chemistry, Seoul National University, Seoul, 08826, Republic of Korea.</li> <li data-affiliation-id="full-view-affiliation-4" id="full-view-affiliation-4" ><sup class="key">4</sup> Plumbline Life Sciences, Inc., Seoul, 06552, Republic of Korea.</li> <li data-affiliation-id="full-view-affiliation-5" id="full-view-affiliation-5" ><sup class="key">5</sup> Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, 10032, USA.</li> <li data-affiliation-id="full-view-affiliation-6" id="full-view-affiliation-6" ><sup class="key">6</sup> School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.</li> <li data-affiliation-id="full-view-affiliation-7" id="full-view-affiliation-7" ><sup class="key">7</sup> Center for RNA Research, Institute for Basic Science, Seoul, 08826, Republic of Korea.</li> <li data-affiliation-id="full-view-affiliation-8" id="full-view-affiliation-8" ><sup class="key">8</sup> Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea. choihj@snu.ac.kr.</li> </ul> </div> </div> </div> <ul class="identifiers" id="full-view-identifiers"> <li> <span class="identifier pubmed"> <span class="id-label"> PMID: </span> <strong class="current-id" title="PubMed ID">33097721</strong> </span> </li> <li> <span class="identifier pmc"> <span class="id-label"> PMCID: </span> <a 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ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Han+W&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Wonhee Han">Wonhee Han</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, 37673, Republic of Korea." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Park+T&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Taeyong Park">Taeyong Park</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Chemistry, Seoul National University, Seoul, 08826, Republic of Korea." href="#short-view-affiliation-3" ref="linksrc=author_aff"> 3 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Kim+EJ&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Eun Jin Kim">Eun Jin Kim</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Plumbline Life Sciences, Inc., Seoul, 06552, Republic of Korea." href="#short-view-affiliation-4" ref="linksrc=author_aff"> 4 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Bang+I&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Injin Bang">Injin Bang</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, 10032, USA." href="#short-view-affiliation-5" ref="linksrc=author_aff"> 5 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Lee+HS&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Hyun Sik Lee">Hyun Sik Lee</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Jeong+Y&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Yejin Jeong">Yejin Jeong</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea." href="#short-view-affiliation-6" ref="linksrc=author_aff"> 6 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Roh+K&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Kyeonghwan Roh">Kyeonghwan Roh</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Kim+J&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Jeesoo Kim">Jeesoo Kim</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Center for RNA Research, Institute for Basic Science, Seoul, 08826, Republic of Korea." href="#short-view-affiliation-7" ref="linksrc=author_aff"> 7 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Kim+JS&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Jong-Seo Kim">Jong-Seo Kim</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a><span class="author-sup-separator"> </span><a class="affiliation-link" title="Center for RNA Research, Institute for Basic Science, Seoul, 08826, Republic of Korea." href="#short-view-affiliation-7" ref="linksrc=author_aff"> 7 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Kang+C&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Chanhee Kang">Chanhee Kang</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea." href="#short-view-affiliation-1" ref="linksrc=author_aff"> 1 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Seok+C&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Chaok Seok">Chaok Seok</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Chemistry, Seoul National University, Seoul, 08826, Republic of Korea." href="#short-view-affiliation-3" ref="linksrc=author_aff"> 3 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Han+JK&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Jin-Kwan Han">Jin-Kwan Han</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, 37673, Republic of Korea." href="#short-view-affiliation-2" ref="linksrc=author_aff"> 2 </a></sup><span class="comma">, </span></span><span class="authors-list-item "><a class="full-name" href="/?term=Choi+HJ&cauthor_id=33097721" ref="linksrc=author_name_link" data-ga-category="search" data-ga-action="author_link" data-ga-label="Hee-Jung Choi">Hee-Jung Choi</a><sup class="affiliation-links"><span class="author-sup-separator"> </span><a class="affiliation-link" title="Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea. choihj@snu.ac.kr." href="#short-view-affiliation-8" ref="linksrc=author_aff"> 8 </a></sup></span> </div> </div> <div class="affiliations"> <h3 class="title"> Affiliations </h3> <ul class="item-list"> <li data-affiliation-id="short-view-affiliation-1" id="short-view-affiliation-1" ><sup class="key">1</sup> Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea.</li> <li data-affiliation-id="short-view-affiliation-2" id="short-view-affiliation-2" ><sup class="key">2</sup> Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk, 37673, Republic of Korea.</li> <li data-affiliation-id="short-view-affiliation-3" id="short-view-affiliation-3" ><sup class="key">3</sup> Department of Chemistry, Seoul National University, Seoul, 08826, Republic of Korea.</li> <li data-affiliation-id="short-view-affiliation-4" id="short-view-affiliation-4" ><sup class="key">4</sup> Plumbline Life Sciences, Inc., Seoul, 06552, Republic of Korea.</li> <li data-affiliation-id="short-view-affiliation-5" id="short-view-affiliation-5" ><sup class="key">5</sup> Department of Physiology and Cellular Biophysics, Columbia University Irving Medical Center, New York, NY, 10032, USA.</li> <li data-affiliation-id="short-view-affiliation-6" id="short-view-affiliation-6" ><sup class="key">6</sup> School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea.</li> <li data-affiliation-id="short-view-affiliation-7" id="short-view-affiliation-7" ><sup class="key">7</sup> Center for RNA Research, Institute for Basic Science, Seoul, 08826, Republic of Korea.</li> <li data-affiliation-id="short-view-affiliation-8" id="short-view-affiliation-8" ><sup class="key">8</sup> Department of Biological Sciences, Seoul National University, Seoul, 08826, Republic of Korea. choihj@snu.ac.kr.</li> </ul> </div> </div> <ul class="identifiers" id="short-view-identifiers"> <li> <span class="identifier pubmed"> <span class="id-label"> PMID: </span> <strong class="current-id" title="PubMed ID">33097721</strong> </span> </li> <li> <span class="identifier pmc"> <span class="id-label"> PMCID: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=PMC7585440&id_type=PMC" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC7585440/" data-ga-category="full_text" data-ga-action="PMCID" > PMC7585440 </a> </span> </li> <li> <span class="identifier doi"> <span class="id-label"> DOI: </span> <a class="id-link" target="_blank" rel="noopener" ref="linksrc=article_id_link&article_id=10.1038/s41467-020-19155-4&id_type=DOI" href="https://doi.org/10.1038/s41467-020-19155-4" data-ga-category="full_text" data-ga-action="DOI" > 10.1038/s41467-020-19155-4 </a> </span> </li> </ul> <div class="in-clipboard-label " hidden> Item in Clipboard </div> </div> </div> </header> <div class="actions-buttons inline"><div class="inner-wrap"><button class="full-text-links-button full-text-links-dialog-trigger" title="Open dialog with 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class="content"><div class="format-container"><span class="option-label"> Format </span><select name="format" data-initial-value="abstract" aria-label="Display format" id="inline-actions-display-format"><option value="abstract">Abstract</option><option value="pubmed">PubMed</option><option value="pmid">PMID</option></select></div></div></div></div></div></div> <div class="linked-articles" id="linked-correction-forward"> <h2 class="title"> Erratum in </h2> <ul class="item-list usa-unstyled-list"> <li class="full-docsum"> <div class="docsum-content" style="display:inline;"> <a class="docsum-title" href="/35110580/" ref="article_id=35110580&linksrc=comments_link" data-ga-category="comment_correction" data-ga-action="abstract_page_link" data-ga-label="linked-correction-forward"> Author Correction: Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains. </a> <div class="docsum-citation full-citation"> <span class="docsum-authors full-authors">Kim J, Han W, Park T, Kim EJ, Bang I, Lee HS, Jeong Y, Roh K, Kim J, Kim JS, Kang C, Seok C, Han JK, Choi HJ.</span> <span class="docsum-authors short-authors">Kim J, et al.</span> <span class="docsum-journal-citation full-journal-citation">Nat Commun. 2022 Feb 2;13(1):738. doi: 10.1038/s41467-022-28394-6.</span> <span class="docsum-journal-citation short-journal-citation">Nat Commun. 2022.</span> <span class="citation-part">PMID: <span class="docsum-pmid">35110580</span></span> <span class="free-resources spaced-citation-item citation-part">Free PMC article.</span> <span class="no-abstract spaced-citation-item citation-part">No abstract available.</span> </div> </div> </li> </ul> </div> <div class="abstract" id="abstract"> <h2 class="title"> Abstract </h2> <div class="abstract-content selected" id="eng-abstract"> <p> Low-density lipoprotein receptor-related protein 6 (LRP6) is a coreceptor of the β-catenin-dependent Wnt signaling pathway. The LRP6 ectodomain binds Wnt proteins, as well as Wnt inhibitors such as sclerostin (SOST), which negatively regulates Wnt signaling in osteocytes. Although LRP6 ectodomain 1 (E1) is known to interact with SOST, several unresolved questions remain, such as the reason why SOST binds to LRP6 E1E2 with higher affinity than to the E1 domain alone. Here, we present the crystal structure of the LRP6 E1E2-SOST complex with two interaction sites in tandem. The unexpected additional binding site was identified between the C-terminus of SOST and the LRP6 E2 domain. This interaction was confirmed by in vitro binding and cell-based signaling assays. Its functional significance was further demonstrated in vivo using Xenopus laevis embryos. Our results provide insights into the inhibitory mechanism of SOST on Wnt signaling. </p> </div> </div> <p class="disclaimer" id="disclaimer"> <a href="/disclaimer/" target="_blank" ga_category="literature_resources" ga_action="disclaimer_link" ga_label="under_abstract">PubMed Disclaimer</a> </p> <div class="conflict-of-interest" id="conflict-of-interest"> <h2 class="title"> Conflict of interest statement </h2> <div class="statement"> <p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one">The authors declare no competing interests.</p> </div> </div> <div class="figures" id="figures"> <h2 class="title"> Figures </h2> <div class="figures-list" id="slides-container" itemscope itemtype="http://schema.org/ImageGallery"> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="0" data-label-slug="fig-1"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad0/7585440/9d3469878ab2/41467_2020_19155_Fig1_HTML.jpg" itemprop="contentUrl" aria-describedby="figure-caption-0" role="button" data-image-width="668" data-image-height="960" data-image-alt="Fig. 1" data-pmc-id="PMC7585440" data-figure-id="Fig1"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-0" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad0/7585440/e7ffea622a64/41467_2020_19155_Fig1_HTML.gif" alt="Fig. 1" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="668"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="960"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 1. Construct design and the crystal… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 1. Construct design and the crystal structure of the LRP6 E1E2–SOST <sub> tr177 </sub> complex. </p> </strong> <div class="figure-caption-contents"><b> a </b> Schematic…</div> </div> <figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 1. Construct design and the crystal structure of the LRP6 E1E2–SOST<sub>tr177</sub> complex. </strong> <div class="figure-caption-contents"><b>a</b> Schematic representations of the LRP6 and SOST constructs. SP signal peptide, P β-propeller domain, EGF epidermal growth factor-like domain, LA LDLR type-A repeats, TM transmembrane domain, CTD C-terminal domain, CK cystine-knot domain. The amino acid residues interacting with LRP6 E1 in the SOST-loop 2 region are shown in dark green. The SOST C-terminal tail sequences including HNQS (orange) and the basic-residue clusters (blue) are also shown. Construct information is described in detail in Supplementary Table 1. <b>b</b> The crystal structure of the LRP6 E1E2–SOST<sub>tr177</sub> complex is represented with a ribbon diagram. For simplicity, only one complex out of two in an asymmetric unit is shown (Supplementary Fig. 4). SOST is colored in magenta, and disulfide bonds are represented as yellow sticks. SOST residues 122–127 are not resolved in this structure and are represented as a dashed line. The LRP6 E1 β-propeller domain is colored in green, and the E2 β-propeller is shown in cyan. The EGF domains are shown in orange.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="1" data-label-slug="fig-2"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad0/7585440/17fa2a1e0252/41467_2020_19155_Fig2_HTML.jpg" itemprop="contentUrl" aria-describedby="figure-caption-1" role="button" data-image-width="683" data-image-height="194" data-image-alt="Fig. 2" data-pmc-id="PMC7585440" data-figure-id="Fig2"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-1" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad0/7585440/fb822909a359/41467_2020_19155_Fig2_HTML.gif" alt="Fig. 2" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="683"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="194"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 2. Canonical binding site of SOST… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 2. Canonical binding site of SOST loop 2 in LRP6 E1. </p> </strong> <div class="figure-caption-contents"><b> a </b> Key interactions…</div> </div> <figcaption id="figure-caption-1" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 2. Canonical binding site of SOST loop 2 in LRP6 E1. </strong> <div class="figure-caption-contents"><b>a</b> Key interactions of the SOST loop 2 region with LRP6 E1 (within 4 Å) are shown with dotted lines. Interacting residues are presented as sticks and are labeled black for LRP6 or magenta for SOST. The missing region of SOST (residues 122–127) in this structure is represented with a dashed line. <b>b</b> Comparison of the SOST loop 2 binding site in our structure with that of the LRP6 E1–SOST peptide complex structure (PDB ID: 3SOV) is presented. The SOST “LPNAIGR” peptide is shown in light gray, and LRP6 E1 from PDB 3SOV is omitted for clarity. The interactions of the NXI motif were found to be conserved in both structures, although the R121-mediated interactions differed. The interactions of R121 in the LRP6 E1-peptide structure are represented with orange dotted lines. <b>c</b> Structural comparison with the LRP6 E1–DKK1 peptide (NSNAIKN) complex (PDB ID: 3SOQ) is shown. The DKK1 peptide is colored in light gray. The interactions of K43 in the LRP6 E1–DKK1 peptide structure are represented in orange dotted lines.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="2" data-label-slug="fig-3"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad0/7585440/5508fe863dc1/41467_2020_19155_Fig3_HTML.jpg" itemprop="contentUrl" aria-describedby="figure-caption-2" role="button" data-image-width="681" data-image-height="201" data-image-alt="Fig. 3" data-pmc-id="PMC7585440" data-figure-id="Fig3"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-2" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad0/7585440/37f537df19ab/41467_2020_19155_Fig3_HTML.gif" alt="Fig. 3" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="681"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="201"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 3. Interaction of SOST C-tail with… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 3. Interaction of SOST C-tail with LRP6 E2. </p> </strong> <div class="figure-caption-contents"><b> a </b> The HNQS motif of the…</div> </div> <figcaption id="figure-caption-2" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 3. Interaction of SOST C-tail with LRP6 E2. </strong> <div class="figure-caption-contents"><b>a</b> The HNQS motif of the SOST C-terminus fits into the binding pocket of the LRP6 E2 β-propeller domain. Interactions of SOST H174 with LRP6 residues are shown with black dotted lines. <b>b</b> The ligand-free state of LRP6 E2 (PDB ID: 3S94; light gray) was aligned to LRP6 E2 (cyan) in our SOST-bound structure. For clarity, SOST was omitted from the overall alignment of LRP6 E2, on the left. Structural changes near W465 and H534 in LRP6 E2 upon SOST binding are shown. H534 of LRP6 moved from the concave center of the β-propeller domain by binding to SOST H174 (colored in magenta in an enlarged box on the right). <b>c</b> The structure of HNQS-bound LRP6 E2 (cyan) was aligned with the structure of loop 2-bound LRP6 E1 (green). The HNQS region is not shown for clarity. Loop 2-interacting residues in LRP6 E1 and corresponding residues in LRP6 E2 are represented as sticks and E2 residues are labeled after the E1 residues.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="3" data-label-slug="fig-4"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad0/7585440/3aac6191b7d6/41467_2020_19155_Fig4_HTML.jpg" itemprop="contentUrl" aria-describedby="figure-caption-3" role="button" data-image-width="681" data-image-height="221" data-image-alt="Fig. 4" data-pmc-id="PMC7585440" data-figure-id="Fig4"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-3" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad0/7585440/dafbfa20f0d0/41467_2020_19155_Fig4_HTML.gif" alt="Fig. 4" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="681"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="221"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 4. Effects of the SOST C-tail… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 4. Effects of the SOST C-tail on LRP6 binding and Wnt1-signaling inhibition. </p> </strong> <div class="figure-caption-contents"><b> a </b> The…</div> </div> <figcaption id="figure-caption-3" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 4. Effects of the SOST C-tail on LRP6 binding and Wnt1-signaling inhibition. </strong> <div class="figure-caption-contents"><b>a</b> The affinities of various SOST mutants for LRP6 E1E2 or LRP6 E1 were measured by MST, and the relative <i>K</i><sub>D</sub> values from those measurements are shown. The <i>K</i><sub>D</sub> value of SOST WT for LRP6 E1E2 was used as a reference. The experimentally determined <i>K</i><sub>D</sub> values are provided in Supplementary Table 2. <b>b</b> The inhibitory effects of SOST mutants on Wnt1 signaling were detected by TopFlash assays. Each luciferase signal observed after co-transfecting plasmids encoding Wnt1 and each SOST mutant was normalized to that found with the empty-vector control. <b>c</b> Differences in the inhibitory activities of SOST with WT LRP6 or the LRP6Δacidic mutant in LRP6-knockout HEK293T cells are shown in the bar graph. Data from three independent experiments (<i>n</i> = 3) were analyzed and expressed as mean ± SEM in <b>b</b> and <b>c</b>.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="4" data-label-slug="fig-5"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad0/7585440/ba4602a4daf8/41467_2020_19155_Fig5_HTML.jpg" itemprop="contentUrl" aria-describedby="figure-caption-4" role="button" data-image-width="674" data-image-height="340" data-image-alt="Fig. 5" data-pmc-id="PMC7585440" data-figure-id="Fig5"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-4" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad0/7585440/c55d5a24a9fd/41467_2020_19155_Fig5_HTML.gif" alt="Fig. 5" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="674"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="340"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 5. Assessing the inhibitory effect of… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 5. Assessing the inhibitory effect of SOST on Wnt signaling in <i> Xenopus </i> embryos. </p> </strong> <div class="figure-caption-contents"><b> a… </b></div> </div> <figcaption id="figure-caption-4" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 5. Assessing the inhibitory effect of SOST on Wnt signaling in <i>Xenopus</i> embryos. </strong> <div class="figure-caption-contents"><b>a</b> The transverse dark-brown line (blue arrow) indicates the normal position of the axis. The yellow arrow indicates the position of the second ectopic axis. Wnt1 induced formation of the second ectopic axis, and successfully inhibiting Wnt resulted in the formation of a single axis. Embryos at the four-cell stage were co-injected in a ventro-vegetal blastomere with 30 pg <i>Wnt1</i> mRNA (<i>n</i> = 104), 25 pg WT <i>SOST</i> mRNA (<i>n</i> = 106), 25 pg <i>SOST</i><sub><i>tr169</i></sub> mRNA (<i>n</i> = 98), 25 pg <i>SOST</i><sub><i>tr177</i></sub> mRNA (<i>n</i> = 119), 25 pg <i>SOST</i><sub><i>tr204</i></sub> mRNA (<i>n</i> = 104), and 25 pg <i>SOST∆loop2</i> mRNA (<i>n</i> = 96) (<i>n</i> number of embryos). <b>b</b> The percentage of embryos with a second axis. The error bars represent the standard error of the mean (SEM) from three independent experiments (<i>n</i> = 3) and <i>p</i> value by two-tailed <i>t</i>-test is indicated. The number of injected embryos is described in <b>a</b>. <b>c</b>, <b>d</b> Real-time qPCR analyses of the expression of genes directly targeted by Wnt1, namely <i>siamois</i> (<b>c</b>) and <i>nodal 3.1</i> (<b>d</b>) from animal cap explants isolated at stage 8 and grown to stage 11. The error bars represent SEMs from three independent experiments (<i>n</i> = 3) and <i>p</i> values by two-tailed <i>t</i>-test are indicated.</div> </figcaption> </figure> <figure class="figure-item " itemscope itemtype="http://schema.org/ImageObject" itemprop="associatedMedia" data-slide-index="5" data-label-slug="fig-6"> <a class="figure-link" href="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad0/7585440/304c1cd924e6/41467_2020_19155_Fig6_HTML.jpg" itemprop="contentUrl" aria-describedby="figure-caption-5" role="button" data-image-width="691" data-image-height="618" data-image-alt="Fig. 6" data-pmc-id="PMC7585440" data-figure-id="Fig6"> <img class="figure-thumb" itemprop="thumbnail" id="article-image-5" src="https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aad0/7585440/d3e167a2deaa/41467_2020_19155_Fig6_HTML.gif" alt="Fig. 6" /> </a> <meta itemprop="width" itemtype="http://schema.org/ImageObject" content="691"> <meta itemprop="height" itemtype="http://schema.org/ImageObject" content="618"> <div class="figure-caption figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="caption" aria-hidden="true"> <div class="caption-wrap"> <strong class="figure-label"> <p> Fig. 6. Proposed mechanism whereby SOST inhibits… </p> </strong> </div> </div> <div class="figure-caption-medium figure-caption-text" aria-hidden="true"> <strong class="figure-label"> <p> Fig. 6. Proposed mechanism whereby SOST inhibits Wnt signaling. </p> </strong> <div class="figure-caption-contents"><p> The inhibitory effects of WT SOST… </p></div> </div> <figcaption id="figure-caption-5" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description"> <strong class="figure-label"> Fig. 6. Proposed mechanism whereby SOST inhibits Wnt signaling. </strong> <div class="figure-caption-contents">The inhibitory effects of WT SOST and SOST mutants on Wnt signaling activated by Wnt1, Wnt2, Wnt9b, and Wnt3a were measured by TopFlash assays. Full-length DKK1 was also used in the activity assays for comparison with SOST. Data from three independent experiments (<i>n</i> = 3) were analyzed and expressed as mean ± SEM. <b>b</b> A schematic model of the mechanism whereby SOST inhibits the canonical Wnt signaling pathway. In a previous model (left), only the loop 2 region of SOST was suggested to interact with the LRP6 E1 domain, which appears to inefficiently inhibit the binding of various Wnt subtypes. The double-headed arrows indicate the wobbling motion of SOST, owing to flexibility in the loop 2 region. On the other hand, the structural and functional data presented here suggest that the C-terminal HNQS region of SOST binds to LRP6 E2, and that the basic cluster region in the far C-terminus of SOST may further strengthen the interaction with the E2 domain. Based on the SOST C-tail-mediated interaction with E2, we propose a new binding model for SOST (right). In this model, tandem interaction of SOST with LRP6 E1 and E2 leads to more efficient blockage of Wnt binding.</div> </figcaption> </figure> </div>  <div class="pswp figures-dialog" id="figures-dialog" tabindex="-1" role="dialog" aria-hidden="true" data-image-gallery-uid="article-figures" aria-label="Figures Dialog">  <div class="pswp__bg"></div>  <div class="pswp__scroll-wrap">  <div class="pswp__container"> <div class="pswp__item"></div> <div class="pswp__item"></div> <div class="pswp__item"></div> </div>  <div class="pswp__ui pswp__ui--hidden"> <div class="pswp__top-bar">  <div class="pswp__counter"></div> <button class="pswp__button pswp__button--close" title="Close (Esc)"></button> <button class="pswp__button pswp__button--share" title="Share"></button> <button class="pswp__button pswp__button--fs" title="Toggle fullscreen"></button> <button class="pswp__button pswp__button--zoom" title="Zoom in/out"></button>   <div class="pswp__preloader"> <div class="pswp__preloader__icn"> <div class="pswp__preloader__cut"> <div class="pswp__preloader__donut"></div> </div> </div> </div> </div> <div class="pswp__share-modal pswp__share-modal--hidden pswp__single-tap"> <div class="pswp__share-tooltip"></div> </div> <button class="pswp__button pswp__button--arrow--left" title="Previous (arrow left)"> </button> <button class="pswp__button pswp__button--arrow--right" title="Next (arrow right)"> </button> <div class="pswp__caption"> <div class="pswp__caption__center"></div> </div> </div> </div> </div> <div class="figure-dialog-caption"> <div class="figure-caption-link-container"> <a class="figure-caption-link" href="#">See this image and copyright information in PMC</a> </div> <div class="figure-caption-center" data-expand-title="click to show full caption" data-collapse-title="click to hide full caption"> </div> <button class="figure-caption-toggle-btn" aria-label="show full caption" data-expand-text="show full caption" data-collapse-text="hide full caption">  </button> </div> </div> <div class="similar-articles" id="similar"> <h2 class="title"> Similar articles </h2> <ul class="articles-list" id="similar-articles-list"> <li class="full-docsum"> <div class="docsum-content" style="display:inline;"> <a class="docsum-title" href="/17002572/" ref="article_id=17002572&linksrc=similar_articles_link&ordinalpos=1" data-ga-category="similar_article" data-ga-action="17002572" data-ga-label=""> Bone density ligand, Sclerostin, directly interacts with LRP5 but not LRP5G171V to modulate Wnt activity. </a> <div class="docsum-citation full-citation"> <span class="docsum-authors full-authors">Ellies DL, Viviano B, McCarthy J, Rey JP, Itasaki N, Saunders S, Krumlauf R.</span> <span class="docsum-authors short-authors">Ellies DL, et al.</span> <span class="docsum-journal-citation full-journal-citation">J Bone Miner Res. 2006 Nov;21(11):1738-49. doi: 10.1359/jbmr.060810.</span> <span class="docsum-journal-citation short-journal-citation">J Bone Miner Res. 2006.</span> <span class="citation-part">PMID: <span class="docsum-pmid">17002572</span></span> </div> </div> </li> <li class="full-docsum"> <div class="docsum-content" style="display:inline;"> <a class="docsum-title" href="/22000856/" ref="article_id=22000856&linksrc=similar_articles_link&ordinalpos=2" data-ga-category="similar_article" data-ga-action="22000856" data-ga-label=""> Structural basis of Wnt signaling inhibition by Dickkopf binding to LRP5/6. </a> <div class="docsum-citation full-citation"> <span class="docsum-authors full-authors">Ahn VE, Chu ML, Choi HJ, Tran D, Abo A, Weis WI.</span> <span class="docsum-authors short-authors">Ahn VE, et al.</span> <span class="docsum-journal-citation full-journal-citation">Dev Cell. 2011 Nov 15;21(5):862-73. doi: 10.1016/j.devcel.2011.09.003. 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Chem. 2009;284:23159–23168. doi: 10.1074/jbc.M109.025478. - <a class="reference-link" href="https://doi.org/10.1074/jbc.m109.025478" ref="linksrc=references_link&ordinalpos=1" data-ga-category="reference" data-ga-action="10.1074/jbc.M109.025478" > DOI </a> - <a class="reference-link" href="https://pmc.ncbi.nlm.nih.gov/articles/PMC2755721/" ref="linksrc=references_link&ordinalpos=2" data-ga-category="reference" data-ga-action="PMC2755721" > PMC </a> - <a class="reference-link" href="/19553665/" ref="linksrc=references_link&ordinalpos=3" data-ga-category="reference" data-ga-action="19553665" > PubMed </a> </li> </ol> </li> </ol> <div class="actions-bar"> <button class="show-all" ref="linksrc=show_all_references_link" aria-controls="top-references-list-1" data-next-page-url="/33097721/references/" data-ga-category="reference" data-ga-action="show_more" > Show all 38 references </button> </div> </div> </div> </div> <div id="publication-types" class="publication-types keywords-section"> <h2 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aria-label="Toggle dropdown menu for keyword Adaptor Proteins, Signal Transducing" tabindex="0" aria-controls="keyword-actions-substances-0" aria-expanded="false" data-pinger-ignore> Adaptor Proteins, Signal Transducing </button><div id="keyword-actions-substances-0" class="keyword-actions-dropdown dropdown dropdown-container" hidden aria-label="Dropdown menu for keyword Adaptor Proteins, Signal Transducing"><div class="title">Actions</div><div class="content"><ul class="keyword-actions-links"><li><a class="search-in-pubmed-link dropdown-block-link" href="/?term=%22Adaptor+Proteins%2C+Signal+Transducing%22%5Bnm%5D&sort=date&sort_order=desc" data-href="/?term=%22Adaptor+Proteins%2C+Signal+Transducing%22%5Bnm%5D&sort=date&sort_order=desc" ref="linksrc=search_in_pubmed_keyword_link&keyword="Adaptor Proteins, Signal Transducing"[nm]" data-ga-category="search" data-ga-action="substance" data-ga-label="Adaptor Proteins, Signal Transducing"> Search in PubMed </a></li><li><a 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Sclerostin inhibits Wnt signaling through tandem interaction with two LRP6 ectodomains - PubMed