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DOI | 10.1038/s41586-018-0455-x |
Structures of beta-klotho reveal a 'zip code'-like mechanism for endocrine FGF signalling | |
Lee, Sangwon1,2; Choi, Jungyuen1,2; Mohanty, Jyotidarsini1,2; Sousa, Leiliane P.1,2; Tome, Francisco1,2; Pardon, Els3; Steyaert, Jan3; Lemmon, Mark A.1,2; Lax, Irit1,2; Schlessinger, Joseph1,2 | |
2018-01-25 | |
发表期刊 | NATURE |
ISSN | 0028-0836 |
EISSN | 1476-4687 |
出版年 | 2018 |
卷号 | 553期号:7689页码:501-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA; Belgium |
英文摘要 | Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation(1,2). By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues(3,4). FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss(5). Endocrine FGFs signal through FGFRs in a manner that requires klothos, which are cell-surface proteins that possess tandem glycosidase domains(3,4). Here we describe the crystal structures of free and ligand-bound beta-klotho extracellular regions that reveal the molecular mechanism that underlies the specificity of FGF21 towards beta-klotho and demonstrate how the FGFR is activated in a klotho-dependent manner. beta-Klotho serves as a primary 'zip code'-like receptor that acts as a targeting signal for FGF21, and FGFR functions as a catalytic subunit that mediates intracellular signalling. Our structures also show how the sugar-cutting enzyme glycosidase has evolved to become a specific receptor for hormones that regulate metabolic processes, including the lowering of blood sugar levels. Finally, we describe an agonistic variant of FGF21 with enhanced biological activity and present structural insights into the potential development of therapeutic agents for diseases linked to endocrine FGFs. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000423971100040 |
WOS关键词 | FIBROBLAST ; RECEPTOR ; BINDING |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/202960 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Yale Sch Med, Dept Pharmacol, 333 Cedar St, New Haven, CT 06520 USA; 2.Yale Sch Med, Yale Canc Biol Inst, 333 Cedar St, New Haven, CT 06520 USA; 3.Vrije Univ Brussel VIB, Ctr Struct Biol, Pl Laan 2, B-1050 Brussels, Belgium |
推荐引用方式 GB/T 7714 | Lee, Sangwon,Choi, Jungyuen,Mohanty, Jyotidarsini,et al. Structures of beta-klotho reveal a 'zip code'-like mechanism for endocrine FGF signalling[J]. NATURE,2018,553(7689):501-+. |
APA | Lee, Sangwon.,Choi, Jungyuen.,Mohanty, Jyotidarsini.,Sousa, Leiliane P..,Tome, Francisco.,...&Schlessinger, Joseph.(2018).Structures of beta-klotho reveal a 'zip code'-like mechanism for endocrine FGF signalling.NATURE,553(7689),501-+. |
MLA | Lee, Sangwon,et al."Structures of beta-klotho reveal a 'zip code'-like mechanism for endocrine FGF signalling".NATURE 553.7689(2018):501-+. |
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