Structural basis for inhibition of the replication licensing factor Cdt1 by geminin

Changwook Lee, BumSoo Hong, Jung Min Choi, Yugene Kim, Saori Watanabe, Yukio Ishimi, Takemi Enomoto, Shusuke Tada, Youngchang Kim and Yunje Cho ()
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Changwook Lee: Pohang University of Science and Technology
BumSoo Hong: Pohang University of Science and Technology
Jung Min Choi: Pohang University of Science and Technology
Yugene Kim: Pohang University of Science and Technology
Saori Watanabe: Tohoku University
Yukio Ishimi: Mitsubishi Kagaku Institute of Life Sciences
Takemi Enomoto: Tohoku University
Shusuke Tada: Tohoku University
Youngchang Kim: Argonne National Laboratory
Yunje Cho: Pohang University of Science and Technology

Nature, 2004, vol. 430, issue 7002, 913-917

Abstract: Abstract To maintain chromosome stability in eukaryotic cells, replication origins must be licensed by loading mini-chromosome maintenance (MCM2–7) complexes once and only once per cell cycle1,2,3,4,5,6,7,8,9. This licensing control is achieved through the activities of geminin10,11,12 and cyclin-dependent kinases9,13,14. Geminin binds tightly to Cdt1, an essential component of the replication licensing system6,15,16,17,18, and prevents the inappropriate reinitiation of replication on an already fired origin. The inhibitory effect of geminin is thought to prevent the interaction between Cdt1 and the MCM helicase19,20. Here we describe the crystal structure of the mouse geminin–Cdt1 complex using tGeminin (residues 79–157, truncated geminin) and tCdt1 (residues 172–368, truncated Cdt1). The amino-terminal region of a coiled-coil dimer of tGeminin interacts with both N-terminal and carboxy-terminal parts of tCdt1. The primary interface relies on the steric complementarity between the tGeminin dimer and the hydrophobic face of the two short N-terminal helices of tCdt1 and, in particular, Pro 181, Ala 182, Tyr 183, Phe 186 and Leu 189. The crystal structure, in conjunction with our biochemical data, indicates that the N-terminal region of tGeminin might be required to anchor tCdt1, and the C-terminal region of tGeminin prevents access of the MCM complex to tCdt1 through steric hindrance.

Date: 2004
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DOI: 10.1038/nature02813

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