ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2017
Modeled structural basis for the recognition of α2-3-sialyllactose by soluble Klotho.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 28 citations in OpenAlex.
- A Controlled Increase in Dietary Phosphate Elevates BP in Healthy Human Subjects.Journal of the American Society of Nephrology : JASN · 2018Trial
- Hederagenin Attenuates Cardiac Remodeling by Targeting Phosphodiesterase 9A.Phytotherapy research : PTR · 2026Article
- Fetuin-A and Heme Oxygenase 1 as Potential New Markers in the Diagnosis of Diabetic Kidney Disease.International journal of molecular sciences · 2025Review
- Overexpression of α-Klotho isoforms promotes distinct Effects on BDNF-Induced Alterations in Dendritic Morphology.Molecular neurobiology · 2024Article
- Phosphate in Cardiovascular Disease: From New Insights Into Molecular Mechanisms to Clinical Implications.Arteriosclerosis, thrombosis, and vascular biology · 2024Review
- KL1 Domain of Longevity Factor Klotho Mimics the Metabolome of Cognitive Stimulation and Enhances Cognition in Young and Aging Mice.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- Novel Markers in Diabetic Kidney Disease-Current State and Perspectives.Diagnostics (Basel, Switzerland) · 2022Review
- Human milk 3'-Sialyllactose is positively associated with language development during infancy.The American journal of clinical nutrition · 2021Article
- Soluble αKlotho downregulates Orai1-mediated store-operated CaPflugers Archiv : European journal of physiology · 2021Article
- Shedding of Klotho: Functional Implications in Chronic Kidney Disease and Associated Vascular Disease.Frontiers in cardiovascular medicine · 2020Review
- Article
- αKlotho-FGF23 interactions and their role in kidney disease: a molecular insight.Cellular and molecular life sciences : CMLS · 2019Review
- Soluble klotho regulates TRPC6 calcium signalingFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- The Klotho proteins in health and disease.Nature reviews. Nephrology · 2019Review
- The role of klotho in chronic kidney disease.BMC nephrology · 2018Review
- Untangling the thread of life spun by αKlotho.Journal of molecular medicine (Berlin, Germany) · 2018Article
- Klotho is upregulated in human cardiomyopathy independently of circulating Klotho levels.Scientific reports · 2018Article
- FGF23 Actions on Target Tissues-With and Without Klotho.Frontiers in endocrinology · 2018Review
- New Insights into the Mechanism of Action of Soluble Klotho.Frontiers in endocrinology · 2017Review
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Authors and funding
9 authors at 3 institutions in 3 countries.
Funding
Abstract
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 binding and recognition of α2-3-sialyllactose 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-regulate TRPC6 channel activity confirm the importance of these residues. Furthermore, KL1 domain binds α2-3-sialyllactose, down-regulates TRPC6 channels, and exerts protection against stress-induced 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.-Wright, J. D., An, S.-W., Xie, J., Yoon, J., Nischan, N., Kohler, J. J., Oliver, N., Lim, C., Huang, C.-L. Modeled structural basis for the recognition of α2-3-sialyllactose by soluble Klotho.
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Registered trials
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