Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University, 26 rue d'Ulm, 75258, Paris cedex 05, France.
Department of Pharmacology & Therapeutics and the Myology Institute, University of Florida College of Medicine, PO Box 100267, Gainesville, Florida, 32610-0267, USA.
Nat Commun. 2023 Oct 23;14(1):6732. doi: 10.1038/s41467-023-42376-2.
Myosin VI (Myo6) is the only minus-end directed nanomotor on actin, allowing it to uniquely contribute to numerous cellular functions. As for other nanomotors, the proper functioning of Myo6 relies on precise spatiotemporal control of motor activity via a poorly defined off-state and interactions with partners. Our structural, functional, and cellular studies reveal key features of myosin regulation and indicate that not all partners can activate Myo6. TOM1 and Dab2 cannot bind the off-state, while GIPC1 binds Myo6, releases its auto-inhibition and triggers proximal dimerization. Myo6 partners thus differentially recruit Myo6. We solved a crystal structure of the proximal dimerization domain, and show that its disruption compromises endocytosis in HeLa cells, emphasizing the importance of Myo6 dimerization. Finally, we show that the L926Q deafness mutation disrupts Myo6 auto-inhibition and indirectly impairs proximal dimerization. Our study thus demonstrates the importance of partners in the control of Myo6 auto-inhibition, localization, and activation.
肌球蛋白 VI（Myo6）是肌动蛋白上唯一的负向指向纳米马达，使其能够独特地贡献于众多细胞功能。与其他纳米马达一样，Myo6 的正常功能依赖于通过定义不明确的非活动状态和与伴侣的相互作用对其运动活性进行精确的时空控制。我们的结构、功能和细胞研究揭示了肌球蛋白调节的关键特征，并表明并非所有的伴侣都能激活 Myo6。TOM1 和 Dab2 不能结合非活动状态，而 GIPC1 结合 Myo6，释放其自动抑制并触发近端二聚化。因此，Myo6 的伴侣以不同的方式募集 Myo6。我们解决了近端二聚化结构域的晶体结构，并表明其破坏会损害 HeLa 细胞的内吞作用，强调了 Myo6 二聚化的重要性。最后，我们表明 L926Q 耳聋突变破坏了 Myo6 的自动抑制，并间接地损害了近端二聚化。因此，我们的研究表明了伴侣在控制 Myo6 自动抑制、定位和激活方面的重要性。
