Abstract
Vertebrate type V myosins (MyoV) Myo5a, Myo5b, and Myo5c mediate transport of several different cargoes. All MyoV paralogs bind to cargo complexes mainly by their C-terminal globular domains. In absence of cargo, the globular domain of Myo5a inhibits its motor domain. Here, we report low-resolution SAXS models for the globular domains from human Myo5a, Myo5b, and Myo5c, which suggest very similar overall shapes of all three paralogs. We determined the crystal structures of globular domains from Myo5a and Myo5b, and provide a homology model for human Myo5c. When we docked the Myo5a crystal structure into a previously published electron microscopy density of the autoinhibited full-length Myo5a, only one domain orientation resulted in a good fit. This structural arrangement suggests the participation of additional region of the globular domain in autoinhibition. Quantification of the interaction of the Myo5a globular domain with its motor complex revealed a tight binding with dissociation half-life in the order of minutes, suggesting a rather slow transition between the active and inactive states.
Highlights
Type V myosin (MyoV) motors move protein complexes, organelles, vesicles, and mRNAs along actin cables [1]
We show by Small Angle X-ray Scattering (SAXS) measurements that the globular domain (GD) of Myo5a, Myo5b, and Myo5c adopt very similar shapes in solution
Small Angle X-ray Scattering (SAXS) experiments with this and corresponding GD fragments of Myo5b and Myo5c showed that these fragments were monodisperse and clearly monomeric in solution (Figure S1 in File S1)
Summary
Type V myosin (MyoV) motors move protein complexes, organelles, vesicles, and mRNAs along actin cables [1]. In contrast to protozoan and invertebrates, mammals have three MyoV paralogs, termed Myo5a, Myo5b, and Myo5c [2]. They share an almost identical domain organization, their expression patterns and cargo specificities show marked differences. Whereas Myo5a is most abundant in neuronal and skin cells [3], Myo5b is found in almost all cell types. A genetic disease called Griscelli syndrome (GS) type I has been linked to mutations in the myo5a gene [6]. Mutations in the myo5b gene of patients are associated with the microvillus inclusion disease [7,8]. No mutation in myo5c has been linked to a heritable syndrome
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