Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 28, Pages 11314-11319Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1306768110
Keywords
myosin V; myo5a; MLPH; RILPL2; granuphilin
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Funding
- Research Grants Council of Hong Kong Grants [663610, 663811, 663812]
- Hong Kong University of Science and Technology [(HKUST)6/CRF/10, SEG_HKUST06, AoE/M-04/04, T13-607/12R]
- [662710]
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Class V myosins (MyoV), the most studied unconventional myosins, recognize numerous cargos mainly via the motor's globular tail domain (GTD). Little is known regarding how MyoV-GTD recognizes such a diverse array of cargos specifically. Here, we solved the crystal structures of MyoVa-GTD in its apo-form and in complex with two distinct cargos, melanophilin and Rab interacting lysosomal protein-like 2. The apo-MyoVa-GTD structure indicates that most mutations found in patients with Griscelli syndrome, microvillus inclusion disease, or cancers or in dilute rodents likely impair the folding of GTD. The MyoVa-GTD/cargo complex structure reveals two distinct cargo-binding surfaces, one primarily via charge-charge interaction and the other mainly via hydrophobic interactions. Structural and biochemical analysis reveal the specific cargo-binding specificities of various isoforms of mammalian MyoV as well as very different cargo recognition mechanisms of MyoV between yeast and higher eukaryotes. The MyoVa-GTD structures resolved here provide a framework for future functional studies of vertebrate class V myosins.
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