biostudies-literatureWright JDNIDDK NIH HHSNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthWelch Foundation3574-3586https://www.ebi.ac.uk/biostudies/studies/S-EPMC5503716biostudies-literatureUnknown31(8)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-regulating calcium-permeable transient receptor potential canonical type isoform 6 (TRPC6) channels in cardiomyocytes and glomerular podocytes. Inhibition of PI3K-dependent exocytosis of TRPC6 is thought to be the underlying mechanism, and recent studies showed that sKlotho interacts with α2-3-sialyllactose-containing gangliosides enriched in lipid rafts to inhibit raft-dependent PI3K signaling. However, the structural basis for bFASEB journal : official publication of the Federation of American Societies for Experimental BiologyModeled structural basis for the recognition of α2-3-sialyllactose by soluble Klotho.PMC5503716I‐1686R01 DK109887DK100605DK109887R01 DK100605Yoon JNischan NAn SWWright JDLim CXie JOliver NKohler JJHuang CLfalseModeled structural basis for the recognition of α2-3-sialyllactose by soluble Klotho.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-regulating calcium-permeable transient receptor potential canonical type isoform 6 (TRPC6) channels in cardiomyocytes and glomerular podocytes. Inhibition of PI3K-dependent exocytosis of TRPC6 is thought to be the underlying mechanism, and recent studies showed that sKlotho interacts with α2-3-sialyllactose-containing gangliosides enriched in lipid rafts to inhibit raft-dependent PI3K signaling. However, the structural basis for b2017-01-01T00:00:00Z2017 Aug2026-05-05T19:43:32.81Z2026-04-07T21:53:07.557ZS-EPMC55037162844254610.1096/fj.201700043R10.1096/fj.201700043r