TY - JOUR
T1 - Soluble klotho regulates TRPC6 calcium signaling via lipid rafts, independent of the FGFR-FGF23 pathway
AU - Wright, Jon D.
AU - An, Sung Wan
AU - Xie, Jian
AU - Lim, Carmay
AU - Huang, Chou Long
N1 - Funding Information:
The authors thank Dr. Lokesh Gakhar and Nicholas Schnicker (Both from the University of Iowa Carver College of Medicine) for comments. The study is supported in part by the U.S. National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (Grants DK100605, DK109887 to C.-L.H.) and by funds from the Ministry of Science & Technology, Taiwan (Grant 106-14) and Academia Sinica, Taiwan (to C.L.). C.-L.H. holds the Roy J. Carver Chair in Internal Medicine in the University of Iowa Carver College of Medicine. The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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-siaryllactose–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. FASEB J. 33, 9182–9193 (2019). www.fasebj.org.
AB - 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-siaryllactose–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. FASEB J. 33, 9182–9193 (2019). www.fasebj.org.
KW - molecular dynamic simulation
KW - sialoganglioside
KW - α2–3-sialyllactose
UR - http://www.scopus.com/inward/record.url?scp=85069648912&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85069648912&partnerID=8YFLogxK
U2 - 10.1096/fj.201900321R
DO - 10.1096/fj.201900321R
M3 - Article
C2 - 31063704
AN - SCOPUS:85069648912
SN - 0892-6638
VL - 33
SP - 9182
EP - 9193
JO - FASEB Journal
JF - FASEB Journal
IS - 8
ER -