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Cryo-EM reveals how human cytoplasmic dynein is auto-inhibited and activated

DOI: 10.1016/j.cell.2017.05.025 DOI Help

Authors: Kai Zhang (MRC Laboratory of Molecular Biology) , Helen E. Foster (MRC Laboratory of Molecular Biology) , Arnaud Rondelet (Max Planck Institute of Molecular Physiology) , Samuel E. Lacey (MRC Laboratory of Molecular Biology) , Nadia Bahi-Buisson (Université Paris Descartes) , Alexander W. Bird (Max Planck Institute of Molecular Physiology) , Andrew P. Carter (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Cell

State: Published (Approved)
Published: June 2017
Diamond Proposal Number(s): 13361

Open Access Open Access

Abstract: Cytoplasmic dynein-1 binds dynactin and cargo adaptor proteins to form a transport machine capable of long-distance processive movement along microtubules. However, it is unclear why dynein-1 moves poorly on its own or how it is activated by dynactin. Here, we present a cryoelectron microscopy structure of the complete 1.4-megadalton human dynein-1 complex in an inhibited state 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 motor 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 directly stimulates its motor activity.

Journal Keywords: motor; dynein; dynactin; cryo-EM; microtubule; phi-particle; auto-inhibition; activation

Subject Areas: Biology and Bio-materials

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Added On: 14/06/2017 08:51


Discipline Tags:

Structural biology Life Sciences & Biotech

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)