Structure of the active form of human origin recognition complex and its ATPase motor module
Ante Tocilj,
Kin Fan On,
Zuanning Yuan,
Jingchuan Sun,
Elad Elkayam,
Huilin Li,
Bruce Stillman,
Leemor Joshua-Tor
Affiliations
Ante Tocilj
W. M. Keck Structural Biology Laboratory, Cold Spring Harbor, New York, United States; Howard Hughes Medical Institute, Cold Spring Harbor, New York, United States; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States
Kin Fan On
W. M. Keck Structural Biology Laboratory, Cold Spring Harbor, New York, United States; Howard Hughes Medical Institute, Cold Spring Harbor, New York, United States; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States
Zuanning Yuan
Biology Department, Brookhaven National Laboratory, New York, United States; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, United States
Jingchuan Sun
Biology Department, Brookhaven National Laboratory, New York, United States
Elad Elkayam
W. M. Keck Structural Biology Laboratory, Cold Spring Harbor, New York, United States; Howard Hughes Medical Institute, Cold Spring Harbor, New York, United States; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States
Huilin Li
Biology Department, Brookhaven National Laboratory, New York, United States; Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, United States
W. M. Keck Structural Biology Laboratory, Cold Spring Harbor, New York, United States; Howard Hughes Medical Institute, Cold Spring Harbor, New York, United States; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, United States
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.
