1. The Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida 32306-4380, USA
2. Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont 05405-0068, USA

Correspondence to: Kathleen M. Trybus²Kenneth A. Taylor¹ Correspondence and requests for materials should be addressed to K.A.T. (Email: taylor@bio.fsu.edu) or K.M.T. (Email: trybus@physiology.med.uvm.edu). The atomic coordinates of the final myoV atomic model have been deposited in the Protein Data Bank with accession number 2DFS. The density volume for the flower motif shown in Fig. 2 has been deposited in the European Bioinformatics Institute under accession code EMD-1201.

Abstract

Unconventional myosin V (myoV) is an actin-based molecular motor that has a key function in organelle and mRNA transport, as well as in membrane trafficking¹. MyoV was the first member of the myosin superfamily shown to be processive, meaning that a single motor protein can 'walk' hand-over-hand along an actin filament for many steps before detaching^{2, 3, 4}. Full-length myoV has a low actin-activated MgATPase activity at low [Ca²⁺], whereas expressed constructs lacking the cargo-binding domain have a high activity regardless of [Ca²⁺] (refs 5–7). Hydrodynamic data and electron micrographs indicate that the active state is extended, whereas the inactive state is compact^{8, 9, 10}. Here we show the first three-dimensional structure of the myoV inactive state. Each myoV molecule consists of two heads that contain an amino-terminal motor domain followed by a lever arm that binds six calmodulins. The heads are followed by a coiled-coil dimerization domain (S2) and a carboxy-terminal globular cargo-binding domain. In the inactive structure, bending of myoV at the head–S2 junction places the cargo-binding domain near the motor domain's ATP-binding pocket, indicating that ATPase inhibition might occur through decreased rates of nucleotide exchange. The actin-binding interfaces are unobstructed, and the lever arm is oriented in a position typical of strong actin-binding states. This structure indicates that motor recycling after cargo delivery might occur through transport on actively treadmilling actin filaments rather than by diffusion.

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