α-Klotho is a non-enzymatic molecular scaffold for FGF23 hormone signalling

被引：435

作者：

Chen, Gaozhi ^{[1
,2
]}

Liu, Yang ^{[2
]}

Goetz, Regina ^{[2
]}

Fu, Lili ^{[1
,2
]}

Jayaraman, Seetharaman ^{[3
]}

Hu, Ming-Chang ^{[4
,5
,6
]}

Moe, Orson W. ^{[4
,5
,6
]}

Liang, Guang ^{[1
]}

Li, Xiaokun ^{[1
]}

Mohammadi, Moosa ^{[2
]}

机构：

[1] Wenzhou Med Univ, Sch Pharmaceut Sci, Chem Biol Res Ctr, Wenzhou 325035, Zhejiang, Peoples R China

[2] NYU, Sch Med, Dept Biochem & Mol Pharmacol, New York, NY 10016 USA

[3] New York Struct Biol Ctr, New York, NY 10027 USA

[4] Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA

[5] Univ Texas Southwestern Med Ctr Dallas, Dept Physiol, Dallas, TX 75390 USA

[6] Univ Texas Southwestern Med Ctr Dallas, Charles & Jane Pak Ctr Mineral Metab & Clin Res, Dallas, TX 75390 USA

来源：

NATURE | 2018年 / 553卷 / 7689期

基金：

国家重点研发计划;

关键词：

FIBROBLAST-GROWTH-FACTOR; TRANSCRIPTS ENCODING MEMBRANE; C-TERMINAL TAIL; STRUCTURAL BASIS; BETA-KLOTHO; FIBROBLAST-GROWTH-FACTOR-1; FGF1; METABOLIC-ACTIVITY; CRYSTAL-STRUCTURE; RECEPTOR; HEPARIN;

D O I：

10.1038/nature25451

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

The ageing suppressor alpha-klotho binds to the fibroblast growth factor receptor (FGFR). This commits FGFR to respond to FGF23, a key hormone in the regulation of mineral ion and vitamin D homeostasis. The role and mechanism of this co-receptor are unknown. Here we present the atomic structure of a 1:1:1 ternary complex that consists of the shed extracellular domain of alpha-klotho, the FGFR1c ligand-binding domain, and FGF23. In this complex, alpha-klotho simultaneously tethers FGFR1c by its D3 domain and FGF23 by its C-terminal tail, thus implementing FGF23-FGFR1c proximity and conferring stability. Dimerization of the stabilized ternary complexes and receptor activation remain dependent on the binding of heparan sulfate, a mandatory cofactor of paracrine FGF signalling. The structure of alpha-klotho is incompatible with its purported glycosidase activity. Thus, shed alpha-klotho functions as an on-demand non-enzymatic scaffold protein that promotes FGF23 signalling.

引用

页码：461 / +

页数：26

共 53 条

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