Abstract
The molecular motor myosin undergoes a series of major structural transitions during its force-producing motor cycle. The underlying mechanism and its coupling to ATP hydrolysis and actin binding are only partially understood, mostly due to sparse structural data on actin-bound states of myosin. Here, we report 26 high-resolution cryo-EM structures of the actomyosin-V complex in the strong-ADP, rigor, and a previously unseen post-rigor transition state that binds the ATP analog AppNHp. The structures reveal a high flexibility of myosin in each state and provide valuable insights into the structural transitions of myosin-V upon ADP release and binding of AppNHp, as well as the actomyosin interface. In addition, they show how myosin is able to specifically alter the structure of F-actin.
Highlights
The molecular motor myosin is well known for its central role in muscle contraction (Hanson & Huxley, 1953; Szent-Györgyi, 2004)
To provide insights into the structural transitions of myosin along its motor cycle, we determined the structure of the actomyosin-V complex in three different nucleotide states using single particle cryo-EM
& Rayment, 2000; Gulick, Bauer, Thoden, & Rayment, 1997) and has been reported to lead to a mixture of a pre- and post-powerstroke conformations in myosin-V (Yengo et al, 2002; Volkmann et al, 2005). These results suggest that AppNHp can potentially mimic both
Summary
The molecular motor myosin is well known for its central role in muscle contraction (Hanson & Huxley, 1953; Szent-Györgyi, 2004). Myosin is key to numerous essential cellular processes including cytokinesis, transcription, signal transduction, cell migration and adhesion, and endo- and exocytosis (Coluccio, 2020; Krendel & Mooseker, 2005) While this variety in functions is well reflected by the diversity of the myosin superfamily (Sellers, 2000), the ATP-dependent force generation mechanism as well as the architecture of the motor domain is shared by all myosins (Cope, Whisstock, Rayment, & Kendrick-Jones, 1996). Myosin-V was shown to be sensitive to the nucleotide state of phalloidinstabilized F-actin, preferring young ATP/ADP-Pi-bound F-actin over aged (post-Pi release). To investigate the structural effect the nucleotide state of F-actin has on myosin-V, we have determined the structure of the rigor complex starting from young ADP-Pi-bound. In addition to these structures and their implications, we report a pronounced conformational heterogeneity of myosin-V in all our data sets and characterize it in detail based on 18 high-resolution subset structures
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