Cryo-EM structures reveal specialization at the myosin VI-actin interface and a mechanism of force sensitivity
Pinar S Gurel,
Laura Y Kim,
Paul V Ruijgrok,
Tosan Omabegho,
Zev Bryant,
Gregory M Alushin
Affiliations
Pinar S Gurel
Laboratory of Structural Biophysics and Mechanobiology, The Rockefeller University, New York, United States; Cell Biology and Physiology Center, National Heart, Blood, and Lung Institute, National Institutes of Health, Bethesda, United States
Laura Y Kim
Cell Biology and Physiology Center, National Heart, Blood, and Lung Institute, National Institutes of Health, Bethesda, United States
Paul V Ruijgrok
Department of Bioengineering, Stanford University, Stanford, United States
Tosan Omabegho
Department of Bioengineering, Stanford University, Stanford, United States
Zev Bryant
Department of Bioengineering, Stanford University, Stanford, United States; Department of Structural Biology, Stanford University, Stanford, United States
Despite extensive scrutiny of the myosin superfamily, the lack of high-resolution structures of actin-bound states has prevented a complete description of its mechanochemical cycle and limited insight into how sequence and structural diversification of the motor domain gives rise to specialized functional properties. Here we present cryo-EM structures of the unique minus-end directed myosin VI motor domain in rigor (4.6 Å) and Mg-ADP (5.5 Å) states bound to F-actin. Comparison to the myosin IIC-F-actin rigor complex reveals an almost complete lack of conservation of residues at the actin-myosin interface despite preservation of the primary sequence regions composing it, suggesting an evolutionary path for motor specialization. Additionally, analysis of the transition from ADP to rigor provides a structural rationale for force sensitivity in this step of the mechanochemical cycle. Finally, we observe reciprocal rearrangements in actin and myosin accompanying the transition between these states, supporting a role for actin structural plasticity during force generation by myosin VI.
