Structure
Volume 20, Issue 4, 4 April 2012, Pages 654-666
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Article
Asymmetric Mode of Ca2+-S100A4 Interaction with Nonmuscle Myosin IIA Generates Nanomolar Affinity Required for Filament Remodeling

https://doi.org/10.1016/j.str.2012.02.002Get rights and content
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Summary

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.

Highlights

► 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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These authors contributed equally to this work

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Present address: Department of Chemistry & Biochemistry, University of California at Santa Cruz, Santa Cruz, CA 95064, USA