Journal
STRUCTURE
Volume 20, Issue 4, Pages 654-666Publisher
CELL PRESS
DOI: 10.1016/j.str.2012.02.002
Keywords
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Funding
- King's College, London
- NIH [AR034711]
- BBSRC
- Wellcome Trust
- North West Cancer Research Fund [CR732]
- Korea Basic Science Institute [T3221A]
- Global Frontier Research grant [NRF-M1AXA002-2011-0031424]
- BBSRC [BB/F00768X/1, BB/F007213/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F00768X/1, BB/F007213/1] Funding Source: researchfish
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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 similar to 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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