The Unique Cysteine Knot Regulates the Pleotropic Hormone Leptin

被引:44
作者
Haglund, Ellinor [1 ,2 ]
Sulkowska, Joanna I. [1 ,2 ]
He, Zhao [3 ,4 ]
Feng, Gen-Sheng [3 ,4 ]
Jennings, Patricia A. [1 ,2 ]
Onuchic, Jose N. [5 ,6 ]
机构
[1] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA
[2] Univ Calif San Diego, Ctr Theoret Biol Phys CTBP, La Jolla, CA 92093 USA
[3] Univ Calif San Diego, Dept Pathol, Sch Med, La Jolla, CA 92093 USA
[4] Univ Calif San Diego, Mol Biol Sect, Div Biol Sci, La Jolla, CA 92093 USA
[5] Rice Univ, Ctr Theoret Biol Phys, Houston, TX USA
[6] Rice Univ, Dept Phys & Astron Chem & Biochem & Cell Biol, Houston, TX USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
INTRACHAIN DISULFIDE BOND; BODY-WEIGHT REGULATION; STRUCTURE-BASED MODELS; OBESE GENE-PRODUCT; OB PROTEIN; MISSENSE MUTATION; CRYSTAL-STRUCTURE; FOOD-INTAKE; DYNAMICS; INTERLEUKIN-1-BETA;
D O I
10.1371/journal.pone.0045654
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
07 ; 0710 ; 09 ;
摘要
Leptin plays a key role in regulating energy intake/expenditure, metabolism and hypertension. It folds into a four-helix bundle that binds to the extracellular receptor to initiate signaling. Our work on leptin revealed a hidden complexity in the formation of a previously un-described, cysteine-knotted topology in leptin. We hypothesized that this unique topology could offer new mechanisms in regulating the protein activity. A combination of in silico simulation and in vitro experiments was used to probe the role of the knotted topology introduced by the disulphide-bridge on leptin folding and function. Our results surprisingly show that the free energy landscape is conserved between knotted and unknotted protein, however the additional complexity added by the knot formation is structurally important. Native state analyses led to the discovery that the disulphide-bond plays an important role in receptor binding and thus mediate biological activity by local motions on distal receptor-binding sites, far removed from the disulphide-bridge. Thus, the disulphide-bridge appears to function as a point of tension that allows dissipation of stress at a distance in leptin.
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页数:13
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