Revealing Auto-inhibition And Activation Mechanism of Human Dynein-1
题目：Revealing Auto-inhibition And Activation Mechanism of Human Dynein-1
报告人：Kai Zhang, Ph.D.
MRC Laboratory of Molecular Biology, UK
Host：北京大学分子医学研究所 陈雷 (Tel. 6275-5557)
摘要: Cytoplasmic dynein-1 binds dynactin in the presence of cargo adaptor proteins to form a transport machine capable of long distance processive movement along microtubules. However, it is unclear why human dynein-1 cannot move on its own and how dynactin activates movement. Here we present a cryo-electron microscopy (cryo-EM) structure of the complete 1.4 MDa human dynein-1 complex in an inhibited conformation known as the phi-particle. We reveal the 3D structure of the cargo binding dynein tail and show how self-dimerization of the motor-domains locks them in a conformation with low microtubule affinity. Disrupting dimerization with structure-based mutagenesis drives dynein-1 into an open-form with higher affinity for both microtubules and dynactin. We find the open-form is also inhibited for movement and that dynactin relieves this by reorienting the motor domains to interact correctly with microtubules. Our model explains how dynactin binding to the dynein-1 tail stimulates its motor activity directly.