{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T11:01:13Z","timestamp":1789383673359,"version":"build-2803163510"},"reference-count":48,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2017,9,19]],"date-time":"2017-09-19T00:00:00Z","timestamp":1505779200000},"content-version":"vor","delay-in-days":49,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK109887"],"award-info":[{"award-number":["DK109887"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK100605"],"award-info":[{"award-number":["DK100605"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000928","name":"Welch Foundation","doi-asserted-by":"publisher","award":["I\u20101686"],"award-info":[{"award-number":["I\u20101686"]}],"id":[{"id":"10.13039\/100000928","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2017,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Soluble Klotho (sKlotho) is the shed ectodomain of antiaging membrane Klotho that contains 2 extracellular domains KL1 and KL2, each of which shares sequence homology to glycosyl hydrolases. sKlotho elicits pleiotropic cellular responses with a poorly understood mechanism of action. Notably, in injury settings, sKlotho confers cardiac and renal protection by down\u2010regulating calcium\u2010permeable transient receptor potential canonical type isoform 6 (TRPC6) channels in cardiomyocytes and glomerular podocytes. Inhibition of PI3K\u2010dependent exocytosis of TRPC6 is thought to be the underlying mechanism, and recent studies showed that sKlotho interacts with \u03b12\u20133\u2010sialyllactose\u2010containing gangliosides enriched in lipid rafts to inhibit raft\u2010dependent PI3K signaling. However, the structural basis for binding and recognition of \u03b12\u20133\u2010sialyllactose by sKlotho is unknown. Using homology modeling followed by docking, we identified key protein residues in the KL1 domain that are likely involved in binding sialyllactose. Functional experiments based on the ability of Klotho to down\u2010regulate TRPC6 channel activity confirm the importance of these residues. Furthermore, KL1 domain binds \u03b12\u20133\u2010sialyllactose, down\u2010regulates TRPC6 channels, and exerts protection against stress\u2010induced cardiac hypertrophy in mice. Our results support the notion that sialogangliosides and lipid rafts are membrane receptors for sKlotho and that the KL1 domain is sufficient for the tested biologic activities. These findings can help guide the design of a simpler Klotho mimetic.\u2014Wright, J. D., An, S.\u2010W., Xie, J., Yoon, J., Nischan, N., Kohler, J. J., Oliver, N., Lim, C., Huang, C.\u2010L. Modeled structural basis for the recognition of \u03b12\u20133\u2010sialyllactose by soluble Klotho.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 31, 3574\u20133586 (2017).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201700043r","type":"journal-article","created":{"date-parts":[[2017,4,25]],"date-time":"2017-04-25T21:00:29Z","timestamp":1493154029000},"page":"3574-3586","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Modeled structural basis for the recognition of \u03b12\u20133\u2010sialyllactose by soluble Klotho"],"prefix":"10.1096","volume":"31","author":[{"given":"Jon D.","family":"Wright","sequence":"first","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sung\u2010Wan","family":"An","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joonho","family":"Yoon","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Nischan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J.","family":"Kohler","sequence":"additional","affiliation":[{"name":"Department of Biochemistry University of Texas Southwestern Medical Center  Dallas Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noelynn","family":"Oliver","sequence":"additional","affiliation":[{"name":"Cardiometabolic Disease Research Boehringer Ingelheim Pharmaceuticals, Inc.  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