Molecular Dynamics Simulations of Forced Unbending of Integrin αVβ3

被引:67
作者
Chen, Wei [1 ]
Lou, Jizhong [2 ]
Hsin, Jen [3 ,4 ]
Schulten, Klaus [3 ,4 ]
Harvey, Stephen C. [2 ,5 ]
Zhu, Cheng [1 ,2 ,6 ]
机构
[1] Georgia Inst Technol, George W Woodruff Sch Mech Engn, Atlanta, GA 30332 USA
[2] Georgia Inst Technol, Inst Bioengn & Biosci, Atlanta, GA 30332 USA
[3] Univ Illinois, Dept Phys, Urbana, IL 61801 USA
[4] Univ Illinois, Beckman Inst, Urbana, IL 61801 USA
[5] Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA
[6] Georgia Inst Technol, Coulter Dept Biomed Engn, Atlanta, GA 30332 USA
关键词
CRYSTAL-STRUCTURE; EXTENDED CONFORMATIONS; EXTRACELLULAR SEGMENT; BETA-3; INTEGRINS; STRUCTURAL BASIS; CATCH BONDS; ACTIVATION; DOMAIN; ALPHA-V-BETA-3; ECTODOMAIN;
D O I
10.1371/journal.pcbi.1001086
中图分类号
Q5 [生物化学];
学科分类号
070307 [化学生物学];
摘要
Integrins may undergo large conformational changes during activation, but the dynamic processes and pathways remain poorly understood. We used molecular dynamics to simulate forced unbending of a complete integrin alpha(V)beta(3) ectodomain in both unliganded and liganded forms. Pulling the head of the integrin readily induced changes in the integrin from a bent to an extended conformation. Pulling at a cyclic RGD ligand bound to the integrin head also extended the integrin, suggesting that force can activate integrins. Interactions at the interfaces between the hybrid and beta tail domains and between the hybrid and epidermal growth factor 4 domains formed the major energy barrier along the unbending pathway, which could be overcome spontaneously in similar to 1 mu s to yield a partially-extended conformation that tended to rebend. By comparison, a fully-extended conformation was stable. A newly-formed coordination between the alpha(V) Asp457 and the alpha-genu metal ion might contribute to the stability of the fully-extended conformation. These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.
引用
收藏
页数:13
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