Asymmetric mode of Ca²⁺-S100A4 interaction with nonmuscle myosin IIA generates nanomolar affinity required for filament remodeling.
Asymmetric mode of Ca²⁺-S100A4 interaction with nonmuscle myosin IIA generates nanomolar affinity required for filament remodeling.
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DOI：
10.1016/j.str.2012.02.002
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发表时间：
2012-04-04
期刊：
影响因子：
5.7
通讯作者：
Barsukov, Igor L.
中科院分区：
文献类型：
--
作者：
Elliott, Paul R.;Irvine, Andrew F.;Jung, Hyun Suk;Tozawa, Kaeko;Pastok, Martyna W.;Picone, Remigio;Badyal, Sandip K.;Basran, Jaswir;Rudland, Philip S.;Barraclough, Roger;Lian, Lu-Yun;Bagshaw, Clive R.;Kriajevska, Marina;Barsukov, Igor L.
非肌肉肌球蛋白IIA（NMIIA）的细丝组装由小的Ca 2+结合蛋白S100A4选择性调节，这导致某些癌症中细胞迁移和转移增强。我们的NMR结构表明，S100A4二聚体结合到一个单一的肌球蛋白重链的不对称配置。复合物中的NMIIA形成一个连续的螺旋，延伸穿过S100A4的表面，并与二聚体中每个亚基的Ca2+依赖性结合位点结合。这些位点之间的协同作用导致S100家族中独特的非常紧密的关联（KD <1 nM）。去除这种协同作用的单残基突变削弱了结合并改善了S100A4对A431人上皮癌细胞中NMIIA细丝组装和细胞扩散的影响。我们提出了一个模型NMIIA细丝拆卸S100A4在初始绑定到非结构化NMIIA尾巴启动解压缩的卷曲螺旋和破坏细丝包装。S100A4二聚体与肌球蛋白IIA单分子以不对称方式结合S100A4中Ca依赖位点之间的协同作用导致高亲和力的相互作用S100A4二聚体与肌球蛋白卷曲螺旋结合S100A4对应力纤维的形成和细胞迁移有直接影响
Filament assembly of nonmuscle myosin IIA (NMIIA) is selectively regulated by the small Ca2+-binding protein, S100A4, which causes enhanced cell migration and metastasis in certain cancers. Our NMR structure shows that an S100A4 dimer binds to a single myosin heavy chain in an asymmetrical configuration. NMIIA in the complex forms a continuous helix that stretches across the surface of S100A4 and engages the Ca2+-dependent binding sites of each subunit in the dimer. Synergy between these sites leads to a very tight association (KD ∼1 nM) that is unique in the S100 family. Single-residue mutations that remove this synergy weaken binding and ameliorate the effects of S100A4 on NMIIA filament assembly and cell spreading in A431 human epithelial carcinoma cells. We propose a model for NMIIA filament disassembly by S100A4 in which initial binding to the unstructured NMIIA tail initiates unzipping of the coiled coil and disruption of filament packing. ► S100A4 dimer binds single-myosin IIA molecule in an asymmetrical mode ► Synergy between Ca-dependent sites in S100A4 leads to high-affinity interaction ► Electron microscopy shows that two S100A4 dimers bind to the myosin coiled coil ► S100A4 has direct effect on formation of stress fibers and cell migration
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影响因子：
2.9
作者：
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通讯作者：
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影响因子：
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通讯作者：
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影响因子：
5.6
作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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