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

ABSTRACT: 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.

SUBMITTER: Elliott PR 

PROVIDER: S-EPMC3343272 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature