Structural insight into the role of thrombospondin-1 binding to calreticulin in calreticulin-induced focal adhesion disassembly.
Structural insight into the role of thrombospondin-1 binding to calreticulin in calreticulin-induced focal adhesion disassembly.
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DOI：
10.1021/bi902067f
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发表时间：
2010-05-04
期刊：
影响因子：
2.9
通讯作者：
Song, Yuhua
中科院分区：
文献类型：
--
作者：
Yan, Qi;Murphy-Ullrich, Joanne E.;Song, Yuhua
血小板反应蛋白-1（TSP-1）与细胞表面钙网蛋白（CRT）结合，刺激CRT与LDL受体相关蛋白（LRP-1）的结合，以发出粘着斑解体和细胞活动参与的信号。这种现象的结构基础尚不清楚。结合结合自由能分析、分子动力学模拟和各向异性网络模型约束的分子动力学模拟，研究了TSP 1-CRT复合物的结合热力学以及与TSP 1结合引起的CRT构象变化。结果表明，TSP 1中的第24位和第32位氨基酸突变为Ala，以及CRT中的第24-26位和第32-34位氨基酸突变为Ala，明显减弱了TSP 1与CRT的结合，这与实验结果一致。在验证计算的TSP 1-CRT复合物的结合亲和力变化的TSP 1和CRT中的关键残基的突变与实验结果后，我们进行了构象分析，以了解TSP 1结合CRT在CRT中诱导构象变化的作用。构象分析表明，TSP 1与CRT的结合导致CRT N-结构域相对于CRT P-结构域的更“开放”构象和显著的旋转变化，这可能暴露CRT中用于结合LRP 1的潜在结合位点以信号粘着斑解体。结果提供了结构洞察的作用TSP 1结合CRT CRT引起的局部粘连解体。
Thrombospondin-1 (TSP1) binding to calreticulin (CRT) on the cell surface stimulates association of CRT with LDL receptor-related protein (LRP1) to signal focal adhesion disassembly and engagement of cellular activities. The structural basis for this phenomenon is unknown. We studied the binding thermodynamics of the TSP1–CRT complex and the conformational changes in CRT induced by binding to TSP1 with combined binding free energy analysis, molecular dynamics simulation, and anisotropic network model restrained molecular dynamics simulation. Results showed that mutations of Lys 24 and Lys 32 in TSP1 to Ala and of amino acids 24–26 and 32–34 in CRT to Ala significantly weakened the binding of TSP1 and CRT, which is consistent with experimental results. Upon validation of the calculated binding affinity changes of the TSP1–CRT complex by mutations in key residues in TSP1 and CRT with the experimental results, we performed conformational analyses to understand the role of TSP1 binding to CRT in the induction of conformational changes in CRT. Conformational analyses showed that TSP1 binding to CRT resulted in a more “open” conformation and a significant rotational change for the CRT N-domain with respect to the CRT P-domain, which could expose the potential binding site(s) in CRT for binding to LRP1 to signal focal adhesion disassembly. Results offer structural insight into the role of TSP1 binding to CRT in CRT-induced focal adhesion disassembly.
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DOI：
10.1038/sj.jidsymp.5650011
发表时间：
2006-09-01
影响因子：
--
作者：
Gold, Leslie I.;Rahman, Mohammad;Cadacio, Caprice L.
通讯作者：
Cadacio, Caprice L.
影响因子：
5.6
作者：
Jin, Ling;Wu, Yingliang
通讯作者：
Wu, Yingliang
DOI：
10.1016/s1359-0278(97)00024-2
发表时间：
1997-01-01
期刊：
FOLDING & DESIGN
影响因子：
--
作者：
Bahar, I;Atilgan, AR;Erman, B
通讯作者：
Erman, B
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
影响因子：
3.5
作者：
Ellgaard, L;Riek, R;Wüthrich, K
通讯作者：
Wüthrich, K