The dynamic nature of the human Origin Recognition Complex revealed through five cryoEM structures
Genome replication is initiated from specific origin sites established by dynamic events. The Origin Recognition Complex (ORC) is necessary for orchestrating the initiation process by binding to origin DNA, recruiting CDC6, and assembling the MCM replicative helicase on DNA. Here we report five cryoEM structures of the human ORC (HsORC) that illustrate the native flexibility of the complex. The absence of ORC1 revealed a compact, stable complex of ORC2-5. Introduction of ORC1 opens the complex into several dynamic conformations. Two structures revealed dynamic movements of the ORC1 AAA+ and ORC2 winged-helix domains that likely impact DNA incorporation into the ORC core. Additional twist and pinch motions were observed in an open ORC conformation revealing a hinge at the ORC5·3 interface that may facilitate ORC binding to DNA. Finally, a structure of ORC was determined with endogenous DNA bound in the core revealing important differences between human and yeast origin recognition.
All coordinates and cryoEM maps have deposited in the PDB and EMDB:ORC-O1AAA:PDB code: 7JPOEMDB code: EMD-22417ORC-O2WH:PDB code: 7JPPEMDB code: EMD-22418ORC-O2-5:PDB code: 7JPQEMDB code: EMD-22419ORC-OPEN:PDB code: 7JPREMDB code: EMD-22420ORC-DNA:PDB code: 7JPSEMDB code: EMD-22421
Article and author information
Howard Hughes Medical Institute (N/A)
- Leemor Joshua-Tor
National Institutes of Health (F32GM129923)
- Matt J Jaremko
National Academies of Sciences, Engineering, and Medicine (GM45436)
- Bruce Stillman
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Sriram Subramaniam, University of British Columbia, Canada
- Received: May 6, 2020
- Accepted: August 17, 2020
- Accepted Manuscript published: August 18, 2020 (version 1)
- Version of Record published: September 2, 2020 (version 2)
© 2020, Jaremko et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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