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S100A4/肌球蛋白-IIA复合物的结构。

Structure of the S100A4/myosin-IIA complex.

作者信息

Ramagopal Udupi A, Dulyaninova Natalya G, Varney Kristen M, Wilder Paul T, Nallamsetty Sridevi, Brenowitz Michael, Weber David J, Almo Steven C, Bresnick Anne R

机构信息

Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.

出版信息

BMC Struct Biol. 2013 Nov 20;13:31. doi: 10.1186/1472-6807-13-31.

DOI:10.1186/1472-6807-13-31
PMID:24252706
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3924328/
Abstract

BACKGROUND

S100A4, a member of the S100 family of Ca2+-binding proteins, modulates the motility of both non-transformed and cancer cells by regulating the localization and stability of cellular protrusions. Biochemical studies have demonstrated that S100A4 binds to the C-terminal end of the myosin-IIA heavy chain coiled-coil and disassembles myosin-IIA filaments; however, the mechanism by which S100A4 mediates myosin-IIA depolymerization is not well understood.

RESULTS

We determined the X-ray crystal structure of the S100A4Δ8C/MIIA(1908-1923) peptide complex, which showed an asymmetric binding mode for the myosin-IIA peptide across the S100A4 dimer interface. This asymmetric binding mode was confirmed in NMR studies using a spin-labeled myosin-IIA peptide. In addition, our NMR data indicate that S100A4Δ8C binds the MIIA(1908-1923) peptide in an orientation very similar to that observed for wild-type S100A4. Studies of complex formation using a longer, dimeric myosin-IIA construct demonstrated that S100A4 binding dissociates the two myosin-IIA polypeptide chains to form a complex composed of one S100A4 dimer and a single myosin-IIA polypeptide chain. This interaction is mediated, in part, by the instability of the region of the myosin-IIA coiled-coil encompassing the S100A4 binding site.

CONCLUSION

The structure of the S100A4/MIIA(1908-1923) peptide complex has revealed the overall architecture of this assembly and the detailed atomic interactions that mediate S100A4 binding to the myosin-IIA heavy chain. These structural studies support the idea that residues 1908-1923 of the myosin-IIA chain heavy represent a core sequence for the S100A4/myosin-IIA complex. In addition, biophysical studies suggest that structural fluctuations within the myosin-IIA coiled-coil may facilitate S100A4 docking onto a single myosin-IIA polypeptide chain.

摘要

背景

S100A4是Ca2+结合蛋白S100家族的成员之一，通过调节细胞突起的定位和稳定性来调控非转化细胞和癌细胞的运动性。生化研究表明，S100A4与肌球蛋白-IIA重链卷曲螺旋的C末端结合并使肌球蛋白-IIA丝解体；然而，S100A4介导肌球蛋白-IIA解聚的机制尚不清楚。

结果

我们确定了S100A4Δ8C/MIIA(1908 - 1923)肽复合物的X射线晶体结构，该结构显示肌球蛋白-IIA肽在S100A4二聚体界面上存在不对称结合模式。使用自旋标记的肌球蛋白-IIA肽进行的核磁共振研究证实了这种不对称结合模式。此外，我们的核磁共振数据表明，S100A4Δ8C以与野生型S100A4非常相似的方向结合MIIA(1908 - 1923)肽。使用更长的二聚体肌球蛋白-IIA构建体进行的复合物形成研究表明，S100A4结合使两条肌球蛋白-IIA多肽链解离，形成由一个S100A4二聚体和一条肌球蛋白-IIA多肽链组成的复合物。这种相互作用部分是由肌球蛋白-IIA卷曲螺旋中包含S100A4结合位点的区域的不稳定性介导的。

结论

S100A4/MIIA(1908 - 1923)肽复合物的结构揭示了该组装体的整体结构以及介导S100A4与肌球蛋白-IIA重链结合的详细原子相互作用。这些结构研究支持了肌球蛋白-IIA链重链的1908 - 1923位残基代表S100A4/肌球蛋白-IIA复合物核心序列的观点。此外，生物物理研究表明，肌球蛋白-IIA卷曲螺旋内的结构波动可能有助于S100A4停靠到一条肌球蛋白-IIA多肽链上。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/05de6faff4a1/1472-6807-13-31-10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/acab94a7997e/1472-6807-13-31-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/320f61b907f0/1472-6807-13-31-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/a875548798a9/1472-6807-13-31-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/68d2e0a68196/1472-6807-13-31-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/405208399c52/1472-6807-13-31-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/de5639932fcb/1472-6807-13-31-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/0e3d3a85d961/1472-6807-13-31-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/d3ec99391103/1472-6807-13-31-8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/4ad03e83e072/1472-6807-13-31-9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/05de6faff4a1/1472-6807-13-31-10.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/acab94a7997e/1472-6807-13-31-1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/320f61b907f0/1472-6807-13-31-2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/a875548798a9/1472-6807-13-31-3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/68d2e0a68196/1472-6807-13-31-4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/405208399c52/1472-6807-13-31-5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/de5639932fcb/1472-6807-13-31-6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/0e3d3a85d961/1472-6807-13-31-7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/d3ec99391103/1472-6807-13-31-8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/4ad03e83e072/1472-6807-13-31-9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b922/3924328/05de6faff4a1/1472-6807-13-31-10.jpg

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