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Structure of human cytoplasmic dynein-2 primed for its power stroke

DOI: 10.1038/nature14023 DOI Help
PMID: 25470043 PMID Help

Authors: Helgo Schmidt (MRC Laboratory of Molecular Biology) , Ruta Zalyte (MRC Laboratory of Molecular Biology) , Linas Urnavicius (MRC Laboratory of Molecular Biology) , Andrew Carter (MRC Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature , VOL 518 , PAGES 435 - 438

State: Published (Approved)
Published: December 2014
Diamond Proposal Number(s): 8547

Open Access Open Access

Abstract: Members of the dynein family, consisting of cytoplasmic and axonemal isoforms, are motors that move towards the minus ends of microtubules. Cytoplasmic dynein-1 (dynein-1) plays roles in mitosis and cellular cargo transport1, and is implicated in viral infections2 and neurodegenerative diseases3. Cytoplasmic dynein-2 (dynein-2) performs intraflagellar transport4 and is associated with human skeletal ciliopathies5. Dyneins share a conserved motor domain that couples cycles of ATP hydrolysis with conformational changes to produce movement6, 7, 8, 9. Here we present the crystal structure of the human cytoplasmic dynein-2 motor bound to the ATP-hydrolysis transition state analogue ADP.vanadate10. The structure reveals a closure of the motor’s ring of six AAA+ domains (ATPases associated with various cellular activites: AAA1–AAA6). This induces a steric clash with the linker, the key element for the generation of movement, driving it into a conformation that is primed to produce force. Ring closure also changes the interface between the stalk and buttress coiled-coil extensions of the motor domain. This drives helix sliding in the stalk which causes the microtubule binding domain at its tip to release from the microtubule. Our structure answers the key questions of how ATP hydrolysis leads to linker remodelling and microtubule affinity regulation.

Subject Areas: Biology and Bio-materials


Instruments: I02-Macromolecular Crystallography

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