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Structure. 2012 Apr 4;20(4):654-66. doi: 10.1016/j.str.2012.02.002. Epub 2012 Apr 3.

Asymmetric mode of Ca²⁺-S100A4 interaction with nonmuscle myosin IIA generates nanomolar affinity required for filament remodeling.

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Institute of Integrative Biology, BioSciences Building, Crown Street, University of Liverpool, Liverpool L69 7ZB, UK.


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.

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