title: Melanophilin Stimulates Myosin-5a Motor Function by Allosterically Inhibiting the Interaction between the Head and Tail of Myosin-5a.
abstract: The tail-inhibition model is generally accepted for the regulation of myosin-5a motor function. Inhibited myosin-5a is in a folded conformation in which its globular tail domain (GTD) interacts with its head and inhibits its motor function, and high Ca(2+) or cargo binding may reduce the interaction between the GTD and the head of myosin-5a, thus activating motor activity. Although it is well established that myosin-5a motor function is regulated by Ca(2+), little is known about the effects of cargo binding. We previously reported that melanophilin (Mlph), a myosin-5a cargo-binding protein, is capable of activating myosin-5a motor function. Here, we report that Mlph-GTBDP, a 26 amino-acid-long peptide of Mlph, is sufficient for activating myosin-5a motor function. We demonstrate that Mlph-GTBDP abolishes the interaction between the head and GTD of myosin-5a, thereby inducing a folded-to-extended conformation transition for myosin-5a and activating its motor function. Mutagenesis of the GTD shows that the GTD uses two distinct, non-overlapping regions to interact with Mlph-GTBDP and the head of myosin-5a. We propose that the GTD is an allosteric protein and that Mlph allosterically inhibits the interaction between the GTD and head of myosin-5a, thereby activating myosin-5a motor function.
authors.affiliation: Group of Cell Motility and Muscle Contraction, State Key Laboratory of Integrated Management of Insect Pests and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Lin-Lin
authors.initials: LL
authors.lastname: Yao
authors.affiliation: Group of Cell Motility and Muscle Contraction, State Key Laboratory of Integrated Management of Insect Pests and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Qing-Juan
authors.initials: QJ
authors.lastname: Cao
authors.affiliation: Group of Cell Motility and Muscle Contraction, State Key Laboratory of Integrated Management of Insect Pests and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Hai-Man
authors.initials: HM
authors.lastname: Zhang
authors.affiliation: Group of Cell Motility and Muscle Contraction, State Key Laboratory of Integrated Management of Insect Pests and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Group of Cell Motility and Muscle Contraction, State Key Laboratory of Integrated Management of Insect Pests and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Group of Cell Motility and Muscle Contraction, State Key Laboratory of Integrated Management of Insect Pests and Rodents, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins; D002460:Cell Line; D051379:Mice; D008958:Models, Molecular; D024701:Myosin Type V / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011993:Recombinant Fusion Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C435724:Mlph protein, mouse; D011993:Recombinant Fusion Proteins; D000251:Adenosine Triphosphatases; D024701:Myosin Type V