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Research Article

Crystal structure of the S100A4–nonmuscle myosin IIA tail fragment complex reveals an asymmetric target binding mechanism

Bence Kiss, Annette Duelli, László Radnai, Katalin A. Kékesi, Gergely Katona, and László Nyitray
  1. aDepartment of Biochemistry, Eötvös Loránd University, H-1117 Budapest, Hungary;
  2. bDepartment of Chemistry and Molecular Biology, University of Gothenburg, SE-40530 Göteborg, Sweden;
  3. cDepartment of Physiology and Neurobiology, and
  4. dLaboratory of Proteomics, Institute of Biology, Eötvös Loránd University, H-1117 Budapest, Hungary

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PNAS first published March 28, 2012; https://doi.org/10.1073/pnas.1114732109
Bence Kiss
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Annette Duelli
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László Radnai
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Katalin A. Kékesi
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Gergely Katona
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  • For correspondence: gergely.katona@cmb.gu.se nyitray@elte.hu
László Nyitray
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  • For correspondence: gergely.katona@cmb.gu.se nyitray@elte.hu
  1. Edited by* James A. Spudich, Stanford University School of Medicine, Stanford, CA, and approved January 19, 2012 (received for review September 7, 2011)

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Abstract

S100A4 is a member of the S100 family of calcium-binding proteins that is directly involved in tumor metastasis. It binds to the nonmuscle myosin IIA (NMIIA) tail near the assembly competence domain (ACD) promoting filament disassembly, which could be associated with increasing metastatic potential of tumor cells. Here, we investigate the mechanism of S100A4–NMIIA interaction based on binding studies and the crystal structure of S100A4 in complex with a 45-residue-long myosin heavy chain fragment. Interestingly, we also find that S100A4 binds as strongly to a homologous heavy chain fragment of nonmuscle myosin IIC as to NMIIA. The structure of the S100A4–NMIIA complex reveals a unique mode of interaction in the S100 family: A single, predominantly α-helical myosin chain is wrapped around the Ca2+-bound S100A4 dimer occupying both hydrophobic binding pockets. Thermal denaturation experiments of coiled-coil forming NMIIA fragments indicate that the coiled-coil partially unwinds upon S100A4 binding. Based on these results, we propose a model for NMIIA filament disassembly: Part of the random coil tailpiece and the C-terminal residues of the coiled-coil are wrapped around an S100A4 dimer disrupting the ACD and resulting in filament dissociation. The description of the complex will facilitate the design of specific drugs that interfere with the S100A4–NMIIA interaction.

  • Ca2+-binding
  • myosin filaments
  • protein–protein interactions
  • cell migration

Footnotes

  • ↵1B.K. and A.D. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. E-mail: gergely.katona{at}cmb.gu.se or nyitray{at}elte.hu.
  • Author contributions: B.K., G.K., and L.N. designed research; B.K., A.D., and K.A.K. performed research; B.K., A.D., L.R., G.K., and L.N. analyzed data; and B.K., A.D., G.K., and L.N. wrote the paper.

  • The authors declare no conflict of interest.

  • *This Direct Submission article had a prearranged editor.

  • Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org (PDB ID code 3ZWH).

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1114732109/-/DCSupplemental.

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Crystal structure of the S100A4–nonmuscle myosin IIA tail fragment complex reveals an asymmetric target binding mechanism
Bence Kiss, Annette Duelli, László Radnai, Katalin A. Kékesi, Gergely Katona, László Nyitray
Proceedings of the National Academy of Sciences Mar 2012, DOI: 10.1073/pnas.1114732109

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Crystal structure of the S100A4–nonmuscle myosin IIA tail fragment complex reveals an asymmetric target binding mechanism
Bence Kiss, Annette Duelli, László Radnai, Katalin A. Kékesi, Gergely Katona, László Nyitray
Proceedings of the National Academy of Sciences Mar 2012, DOI: 10.1073/pnas.1114732109
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