Institute of Integrative Biology, BioSciences Building, Crown Street, University of Liverpool, Liverpool L69 7ZB, UK.
Structure. 2012 Apr 4;20(4):654-66. doi: 10.1016/j.str.2012.02.002. Epub 2012 Apr 3.
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 (K(D) ∼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.
非肌肉肌球蛋白 IIA（NMIIA）的丝组装被小 Ca²⁺结合蛋白 S100A4 选择性调节，这导致某些癌症中的细胞迁移和转移增强。我们的 NMR 结构显示，S100A4 二聚体以非对称构象结合到单个肌球蛋白重链上。复合物中的 NMIIA 形成一条连续的螺旋，横跨 S100A4 的表面，并与二聚体每个亚基的 Ca²⁺依赖性结合位点结合。这些位点之间的协同作用导致非常紧密的结合（K(D)∼1 nM），这在 S100 家族中是独特的。消除这种协同作用的单残基突变会削弱结合，并减轻 S100A4 对 NMIIA 丝组装和 A431 人上皮癌细胞中细胞铺展的影响。我们提出了一个由 S100A4 介导的 NMIIA 丝解组装模型，其中与无规卷曲 NMIIA 尾巴的初始结合启动了卷曲螺旋的解旋和丝组装的破坏。
