Abstract
SummaryFilament 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
Many fundamental processes in cells such as adhesion, migration, and proliferation are force dependent
The intracellular force is generated by nonmuscle myosin II (NMII), which is ubiquitously expressed in eukaryotic cells (Vicente-Manzanares et al, 2009)
We used NMR to demonstrate that the unstructured region F1926–A1939 that immediately follows the coiled-coil region is essential for the interaction with S100A4 (Badyal et al, 2011)
Summary
Many fundamental processes in cells such as adhesion, migration, and proliferation are force dependent. Adhesion complexes are established under the influence of tension and coordinate traction for cell propulsion. The intracellular force is generated by nonmuscle myosin II (NMII), which is ubiquitously expressed in eukaryotic cells (Vicente-Manzanares et al, 2009). Recent studies in several cell lines, such as CHOK1, COS-7, and B16, showed that NMIIA is more dynamic and is involved in the initial adhesion stages at the leading edge of the cell, as well as the force-controlled disassembly of the adhesion complexes at the trailing edge. NMIIB is mainly localized in the central zones and the cell rear, where it generates persistent tension required for the maintenance of stable adhesions (Vicente-Manzanares et al, 2007)
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