{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T08:19:31Z","timestamp":1780474771052,"version":"3.54.1"},"reference-count":61,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2017,4,20]],"date-time":"2017-04-20T00:00:00Z","timestamp":1492646400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22590061"],"award-info":[{"award-number":["22590061"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2017,6]]},"abstract":"<jats:p>Snake venom metalloproteases (<jats:styled-content style=\"fixed-case\">SVMP<\/jats:styled-content>s) are members of the a disintegrin and metalloprotease (<jats:styled-content style=\"fixed-case\">ADAM<\/jats:styled-content>) family of proteins, as they possess similar domains. <jats:styled-content style=\"fixed-case\">SVMP<\/jats:styled-content>s are known to elicit snake venom\u2010induced haemorrhage; however, the target proteins and cleavage sites are not known. In this work, we identified a target protein of vascular apoptosis\u2010inducing protein 1 (<jats:styled-content style=\"fixed-case\">VAP<\/jats:styled-content>1), an <jats:styled-content style=\"fixed-case\">SVMP<\/jats:styled-content>, relevant to its ability to induce haemorrhage. <jats:styled-content style=\"fixed-case\">VAP<\/jats:styled-content>1 disrupted cell\u2013cell adhesions by relocating <jats:styled-content style=\"fixed-case\">VE<\/jats:styled-content>\u2010cadherin and \u03b3\u2010catenin from the cell\u2013cell junction to the cytosol, without inducing proteolysis of <jats:styled-content style=\"fixed-case\">VE<\/jats:styled-content>\u2010cadherin. The Wnt receptors low\u2010density lipoprotein receptor\u2010related proteins 5 and 6 (<jats:styled-content style=\"fixed-case\">LRP<\/jats:styled-content>5\/6) are known to promote catenin relocation, and are rendered constitutively active in Wnt signalling by truncation. Thus, we examined whether <jats:styled-content style=\"fixed-case\">VAP<\/jats:styled-content>1 cleaves <jats:styled-content style=\"fixed-case\">LRP<\/jats:styled-content>5\/6 to induce catenin relocation. Indeed, we found that <jats:styled-content style=\"fixed-case\">VAP<\/jats:styled-content>1 cleaved the extracellular region of <jats:styled-content style=\"fixed-case\">LRP<\/jats:styled-content>6 and <jats:styled-content style=\"fixed-case\">LRP<\/jats:styled-content>5. This cleavage removes four inhibitory \u03b2\u2010propeller structures, resulting in activation of <jats:styled-content style=\"fixed-case\">LRP<\/jats:styled-content>5\/6. Recombinant human <jats:styled-content style=\"fixed-case\">ADAM<\/jats:styled-content>8 and <jats:styled-content style=\"fixed-case\">ADAM<\/jats:styled-content>12 also cleaved <jats:styled-content style=\"fixed-case\">LRP<\/jats:styled-content>6 at the same site. An antibody against a peptide including the <jats:styled-content style=\"fixed-case\">LRP<\/jats:styled-content>6\u2010cleavage site inhibited <jats:styled-content style=\"fixed-case\">VAP<\/jats:styled-content>1\u2010induced <jats:styled-content style=\"fixed-case\">VE<\/jats:styled-content>\u2010cadherin relocation and disruption of cell\u2013cell adhesions in cultured cells, and blocked haemorrhage in mice <jats:italic>in vivo<\/jats:italic>. Intriguingly, animals resistant to the effects of haemorrhagic snake venom express variants of <jats:styled-content style=\"fixed-case\">LRP<\/jats:styled-content>5\/6 that lack the <jats:styled-content style=\"fixed-case\">VAP<\/jats:styled-content>1\u2010cleavage site, or low\u2010density lipoprotein receptor domain class A domains involved in formation of the constitutively active form. The results validate <jats:styled-content style=\"fixed-case\">LRP<\/jats:styled-content>5\/6 as physiological targets of <jats:styled-content style=\"fixed-case\">ADAM<\/jats:styled-content>s. Furthermore, they indicate that <jats:styled-content style=\"fixed-case\">SVMP<\/jats:styled-content>\u2010induced cleavage of <jats:styled-content style=\"fixed-case\">LRP<\/jats:styled-content>5\/6 causes disruption of cell\u2013cell adhesion and haemorrhage, potentially opening new avenues for the treatment of snake bites.<\/jats:p>","DOI":"10.1111\/febs.14066","type":"journal-article","created":{"date-parts":[[2017,4,20]],"date-time":"2017-04-20T05:04:52Z","timestamp":1492664692000},"page":"1657-1671","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Haemorrhagic snake venom metalloproteases and human <scp>ADAM<\/scp>s cleave <scp>LRP<\/scp>5\/6, which disrupts cell\u2013cell adhesions <i>in vitro<\/i> and induces haemorrhage <i>in vivo<\/i>"],"prefix":"10.1111","volume":"284","author":[{"given":"Tadahiko","family":"Seo","sequence":"first","affiliation":[{"name":"Sugashima Marine Biological Laboratory Graduate 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