Mechanistic insights into the active site and allosteric communication pathways in human nonmuscle myosin-2C.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 29256864.
- Also identified by DOI 10.7554/eLife.32742 and PMC identifier 5749951.
- Licence recorded as CC0.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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⋅VO<sub>4</sub>) 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.
Medical subject headings
- Catalytic Domain
- Myosin Type II