Conversion between three conformational states of integrin I domains with a C-terminal pull spring studied with molecular dynamics
Conversion between three conformational states of integrin I domains with a C-terminal pull spring studied with molecular dynamics
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DOI：
10.1016/j.str.2004.10.005
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发表时间：
2004-12-01
期刊：
影响因子：
5.7
通讯作者：
Springer, TA
中科院分区：
文献类型：
--
作者：
Jin, M;Andricioaei, L;Springer, TA
我们用分子动力学测试了以下假设：整合素中的域间力，通过连接到整合素 I 结构域 C 端 α7 螺旋的弹簧进行模拟，可以变构稳定替代 I 结构域构象。根据施加的力和时间进程，在 alpha(L) 和 alpha(M) I 域中，beta6-alpha7 环在三个棘轮位置之间连续移动；即从封闭到中间，再到开放。 MIDAS 环和金属配位中更远端的连锁变化与 MIDAS 连接时所见的变化非常相似。模拟表明，与 alpha(M) I 域相比，α(L) 域在更广泛的力范围内填充了中间态。对突变体 I 结构域的模拟表明，特定的棘轮残基调节构象平衡。 α(1) 和 α(2) I 结构域的模拟显示，由于第二个棘轮残基处的 Phe 被 Glu 取代，因此缺乏中间构象。这些发现对整合素粘附性的生物调节具有重要意义。
We test with molecular dynamics the hypothesis that interdomain forces in integrins, simulated with a spring attached to the C-terminal alpha7-helix of an integrin I domain, can allosterically stabilize alternative I domain conformations. Depending on the force applied and timecourse, in alpha(L) and alpha(M) I domains the beta6-alpha7 loop moves successively between three ratchet positions; i.e. from closed to intermediate, and then to open. More distal, linked alterations in MIDAS loops and metal coordination closely resemble those seen when the MIDAS becomes ligated. Simulations show that the intermediate state is populated over a wider range of forces for alpha(L) than alpha(M) I domains. Simulations with mutant I domains suggest that specific ratchet residues regulate conformational equilibria. Simulations with alpha(1) and alpha(2) I domains reveal a lack of the intermediate conformation, owing to Phe to Glu substitution at the second ratchet residue. The findings have important implications for biological regulation of integrin adhesiveness.