Soluble klotho regulates TRPC6 calcium signaling via lipid rafts, independent of the FGFR-FGF23 pathway

Jon D. Wright, Sung Wan An, Jian Xie, Carmay Lim, Chou-Long Huang

Research output: Contribution to journalArticle

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Abstract

Soluble klotho (sKlotho), the shed ectodomain of α-klotho, protects the heart by down-regulating transient receptor potential canonical isoform 6 (TRPC6)-mediated calcium signaling. Binding to α2-3-sialyllactose moiety of gangliosides in lipid rafts and inhibition of raft-dependent signaling underlies the mechanism. A recent 3-Å X-ray structure of sKlotho in complex with fibroblast growth factor receptor (FGFR) and fibroblast growth factor 23 (FGF23) indicates that its β6α6 loop might block access to the proposed binding site for α2-3-sialyllactose. It was concluded that sKlotho only functions in complex with FGFR and FGF23 and that sKlotho's pleiotropic effects all depend on FGF23. Here, we report that sKlotho can inhibit TRPC6 channels expressed in cells lacking endogenous FGFRs. Structural modeling and molecular docking show that a repositioned β6α6 loop allows sKlotho to bind α2-3-sialyllactose. Molecular dynamic simulations further show the α2-3-sialyllactose-bound sKlotho complex to be stable. Domains mimicking sKlotho's sialic acid-recognizing activity inhibit TRPC6. The results strongly support the hypothesis that sKlotho can exert effects independent of FGF23 and FGFR.-Wright, J. D., An, S.-W., Xie, J., Lim, C., Huang, C.-L. Soluble klotho regulates TRPC6 calcium signaling via lipid rafts, independent of the FGFR-FGF23 pathway.

Original languageEnglish (US)
Pages (from-to)9182-9193
Number of pages12
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number8
DOIs
StatePublished - Aug 1 2019

Fingerprint

Fibroblast Growth Factor Receptors
Calcium Signaling
Protein Isoforms
Calcium
Lipids
Gangliosides
N-Acetylneuraminic Acid
Molecular Dynamics Simulation
Molecular dynamics
Binding Sites
X-Rays
fibroblast growth factor 23
X rays
3'-sialyllactose
Computer simulation

Keywords

  • molecular dynamic simulation
  • sialoganglioside
  • α2-3-sialyllactose

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Soluble klotho regulates TRPC6 calcium signaling via lipid rafts, independent of the FGFR-FGF23 pathway. / Wright, Jon D.; An, Sung Wan; Xie, Jian; Lim, Carmay; Huang, Chou-Long.

In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 33, No. 8, 01.08.2019, p. 9182-9193.

Research output: Contribution to journalArticle

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