Mechanistic insights into the active site and allosteric communication pathways in human nonmuscle myosin-2C

Author:

Chinthalapudi Krishna123,Heissler Sarah M14,Preller Matthias15ORCID,Sellers James R4ORCID,Manstein Dietmar J12ORCID

Affiliation:

1. Institute for Biophysical Chemistry, OE4350, Hannover Medical School, Hannover, Germany

2. Division for Structural Biochemistry, OE8830, Hannover Medical School, Hannover, Germany

3. Cell Adhesion Laboratory, Department of Integrative Structural and Computational Biology, The Scripps Research Institute, Jupiter, United States

4. Laboratory of Molecular Physiology, NHLBI, National Institutes of Health, Bethesda, United States

5. Centre for Structural Systems Biology (CSSB), German Electron Synchrotron (DESY), Hamburg, Germany

Abstract

Despite a generic, highly conserved motor domain, ATP turnover kinetics and their activation by F-actin vary greatly between myosin-2 isoforms. Here, we present a 2.25 Å pre-powerstroke state (ADP⋅VO4) crystal structure of the human nonmuscle myosin-2C motor domain, one of the slowest myosins characterized. In combination with integrated mutagenesis, ensemble-solution kinetics, and molecular dynamics simulation approaches, the structure reveals an allosteric communication pathway that connects the distal end of the motor domain with the active site. Disruption of this pathway by mutation of hub residue R788, which forms the center of a cluster of interactions connecting the converter, the SH1-SH2 helix, the relay helix, and the lever, abolishes nonmuscle myosin-2 specific kinetic signatures. Our results provide insights into structural changes in the myosin motor domain that are triggered upon F-actin binding and contribute critically to the mechanochemical behavior of stress fibers, actin arcs, and cortical actin-based structures.

Funder

Deutsche Forschungsgemeinschaft

National Institutes of Health

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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