Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.
Proc Natl Acad Sci U S A. 2013 Jul 9;110(28):11314-9. doi: 10.1073/pnas.1306768110. Epub 2013 Jun 24.
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.
V 类肌球蛋白（MyoV）是研究最为深入的非传统肌球蛋白，主要通过其球状尾部结构域（GTD）识别多种货物。然而，目前尚不清楚 MyoV-GTD 如何特异性识别如此多样化的货物。在此，我们解析了 apo 态和与两种不同货物（黑素瘤磷蛋白和 Rab 相互作用溶酶体蛋白样 2）结合态的 MyoVa-GTD 的晶体结构。apo-MyoVa-GTD 结构表明，Grisseli 综合征、微绒毛包涵体病或癌症患者中发现的大多数突变，或“稀释”啮齿动物中的突变，很可能会损害 GTD 的折叠。MyoVa-GTD/货物复合物结构揭示了两个不同的货物结合表面，一个主要通过电荷-电荷相互作用，另一个主要通过疏水相互作用。结构和生化分析揭示了哺乳动物 MyoV 的各种同工型的特定货物结合特异性，以及酵母和高等真核生物中 MyoV 之间非常不同的货物识别机制。本文解析的 MyoVa-GTD 结构为脊椎动物 V 类肌球蛋白的未来功能研究提供了框架。
