How Myosin Generates Force on Actin Filaments. Issue 12 (December 2016)

• Record Type: Journal Article
• Authors: Houdusse, Anne; Sweeney, H. Lee
• Is Part Of: Trends in biochemical sciences. Volume 41:Issue 12(2016)
• Page Start: 989
• Page End: 997
• Publication Date: 2016-12
• Subjects: molecular motors -- allostery -- force generation -- chemo-mechanical transduction; Biochemistry -- Periodicals; 572
• DOI: 10.1016/j.tibs.2016.09.006
• Languages: English
• ISSNs: 0968-0004

Abstract

Abstract : How myosin interacts with actin to generate force is a subject of considerable controversy. The major debate centers on understanding at what point in force generation the inorganic phosphate is released with respect to the lever arm swing, or powerstroke. Resolving the controversy is essential for understanding how force is produced as well as the mechanisms underlying disease-causing mutations in myosin. Recent structural insights into the powerstroke have come from a high-resolution structure of myosin in a previously unseen state and from an electron cryomicroscopy (cryo-EM) 3D reconstruction of the actin–myosin–MgADP complex. Here, we argue that seemingly contradictory data from time-resolved fluorescence resonance energy transfer (FRET) studies can be reconciled, and we put forward a model for myosin force generation on actin. Trends: A new high-resolution structure reveals rearrangements in the myosin motor that promote release of inorganic phosphate (following ATP hydrolysis). FRET experiments reveal that, following binding to actin, the movement of the myosin lever arm (powerstroke) is extremely rapid and faster than the rate of release of inorganic phosphate into solution. Mutagenesis experiments suggest that phosphate release occurs before closure of the actin-binding cleft. Whether the myosin lever arm is coupled to closure of the actin-binding cleft and precedes or follows the release of inorganic phosphate is controversial. Resolving this controversy is central to understanding chemomechanical force transduction by the myosin motor on actin. We present a new model in which phosphate must move out of the active site before closure of the actin-binding cleft coupled to the lever arm swing. However, the phosphate can transiently remain bound to a second binding site at the mouth of the release tunnel, thus delaying its detection in solution.