4.7 Article

Asymmetric Mode of Ca2+-S100A4 Interaction with Nonmuscle Myosin IIA Generates Nanomolar Affinity Required for Filament Remodeling

Journal

STRUCTURE
Volume 20, Issue 4, Pages 654-666

Publisher

CELL PRESS
DOI: 10.1016/j.str.2012.02.002

Keywords

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Funding

  1. King's College, London
  2. NIH [AR034711]
  3. BBSRC
  4. Wellcome Trust
  5. North West Cancer Research Fund [CR732]
  6. Korea Basic Science Institute [T3221A]
  7. Global Frontier Research grant [NRF-M1AXA002-2011-0031424]
  8. BBSRC [BB/F00768X/1, BB/F007213/1] Funding Source: UKRI
  9. 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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