Structure of the active form of human Origin Recognition Complex and its ATPase motor module

  1. Ante Tocilj
  2. Kin Fan On
  3. Zuanning Yuan
  4. Jingchuan Sun
  5. Elad Elkayam
  6. Huilin Li
  7. Bruce Stillman  Is a corresponding author
  8. Leemor Joshua-Tor  Is a corresponding author
  1. Cold Spring Harbor Laboratory, United States
  2. Cold Spring Harbor Laboratory/HHMI, United States
  3. Brookhaven National Laboratory/Stony Brook University, United States
  4. Brookhaven National Laboratory, United States
  5. Van Andel Research Institute, United States

Abstract

Binding of the Origin Recognition Complex (ORC) to origins of replication marks the first step in the initiation of replication of the genome in all eukaryotic cells. Here, we report the structure of the active form of human ORC determined by X-ray crystallography and cryo-electron microscopy. The complex is composed of an ORC1/4/5 motor module lobe in an organization reminiscent of the DNA polymerase clamp loader complexes. A second lobe contains the ORC2/3 subunits. The complex is organized as a double-layered shallow corkscrew, with the AAA+ and AAA+-like domains forming one layer, and the winged-helix domains (WHDs) forming a top layer. CDC6 fits easily between ORC1 and ORC2, completing the ring and the DNA-binding channel, forming an additional ATP hydrolysis site. Analysis of the ATPase activity of the complex provides a basis for understanding ORC activity as well as molecular defects observed in Meier-Gorlin Syndrome mutations.

Article and author information

Author details

  1. Ante Tocilj

    Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kin Fan On

    Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory/HHMI, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Zuanning Yuan

    Biology Department, Brookhaven National Laboratory/Stony Brook University, Upton/Stony Brook, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jingchuan Sun

    Biology Department, Brookhaven National Laboratory, Upton, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Elad Elkayam

    Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory/HHMI, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Huilin Li

    H. Li Lab, Van Andel Research Institute, Grand Rapids, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Bruce Stillman

    Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    For correspondence
    stillman@cshl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9453-4091
  8. Leemor Joshua-Tor

    Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory/HHMI, Cold Spring Harbor, United States
    For correspondence
    leemor@cshl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8185-8049

Funding

Howard Hughes Medical Institute

  • Ante Tocilj

National Institute of General Medical Sciences (GM45436)

  • Bruce Stillman

National Cancer Institute (PO1-CA13016)

  • Ante Tocilj

National Institute of General Medical Sciences (GM111742)

  • Huilin Li

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2017, Tocilj 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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  1. Ante Tocilj
  2. Kin Fan On
  3. Zuanning Yuan
  4. Jingchuan Sun
  5. Elad Elkayam
  6. Huilin Li
  7. Bruce Stillman
  8. Leemor Joshua-Tor
(2017)
Structure of the active form of human Origin Recognition Complex and its ATPase motor module
eLife 6:e20818.
https://doi.org/10.7554/eLife.20818

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https://doi.org/10.7554/eLife.20818