Structure of the S100A4/myosin-IIA complex

Udupi A. Ramagopal, Natalya G. Dulyaninova, Kristen M. Varney, Paul T. Wilder, Sridevi Nallamsetty, Michael Brenowitz, David J. Weber, Steven C. Almo, Anne R. Bresnick

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Background: S100A4, a member of the S100 family of Ca§ssup§ 2+§esup§-binding proteins, modulates the motility of both non-transformed and cancer cells by regulating the localization and stability of cellular protrusions. Biochemical studies have demonstrated that S100A4 binds to the C-terminal end of the myosin-IIA heavy chain coiled-coil and disassembles myosin-IIA filaments; however, the mechanism by which S100A4 mediates myosin-IIA depolymerization is not well understood. Results: We determined the X-ray crystal structure of the S100A4Δ8C/MIIA§ssup§1908- 1923§esup§ peptide complex, which showed an asymmetric binding mode for the myosin-IIA peptide across the S100A4 dimer interface. This asymmetric binding mode was confirmed in NMR studies using a spin-labeled myosin-IIA peptide. In addition, our NMR data indicate that S100A4Δ8C binds the MIIA§ssup§1908-1923§esup§ peptide in an orientation very similar to that observed for wild-type S100A4. Studies of complex formation using a longer, dimeric myosin-IIA construct demonstrated that S100A4 binding dissociates the two myosin-IIA polypeptide chains to form a complex composed of one S100A4 dimer and a single myosin-IIA polypeptide chain. This interaction is mediated, in part, by the instability of the region of the myosin-IIA coiled-coil encompassing the S100A4 binding site. Conclusion: The structure of the S100A4/MIIA§ssup§1908-1923§esup§ peptide complex has revealed the overall architecture of this assembly and the detailed atomic interactions that mediate S100A4 binding to the myosin-IIA heavy chain. These structural studies support the idea that residues 1908-1923 of the myosin-IIA chain heavy represent a core sequence for the S100A4/myosin-IIA complex. In addition, biophysical studies suggest that structural fluctuations within the myosin-IIA coiled-coil may facilitate S100A4 docking onto a single myosin-IIA polypeptide chain.

Original languageEnglish (US)
Article number31
JournalBMC Structural Biology
Issue number1
StatePublished - Nov 20 2013


  • Coiled-coil
  • Cytoskeleton
  • Myosin-II
  • NMR
  • S100A4
  • X-ray crystallography

ASJC Scopus subject areas

  • Structural Biology


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