The middle winged helix fold of replication licensing factor Cdt1 binds geminin to inhibit binding of the MCM complex to origins of replication and DNA
Cdt1 is a replication licensing factor in eukaryotes that recruits the Minichromosome Maintenance Complex (MCM2-7) to the origin recognition complex (ORC). The Cdt1 protein is divided into three regions based on sequence comparison and biochemical analyses: the N-terminal region (Cdt1_n) binds DNA in a sequence-, strand-, and conformation-independent manner; the middle winged helix fold (Cdt1_m) binds geminin to inhibit both binding of the MCM complex to origins of replication and DNA; and the C-terminal region (Cdt1_c) is essential for Cdt1 activity and directly interacts with the MCM2-7 helicase. Precise duplication of chromosomal DNA is required for genomic stability during replication. Assembly of replication factors to start DNA replication in eukaryotes must occur only once per cell cycle. To form a pre-replicative complex on replication origins in the G phase, ORC first binds origin DNA and triggers the binding of Cdc6 and Cdt1. These two factors recruit a putative replicative helicase and the MCM2-7. The MCM2-7 complex promotes the unwinding of DNA origins, and the binding of additional factors to initiate the DNA replication in S-phase. Cdt1 is present during G1 and early S phase of the cell cycle and degraded during the late S, G2, and M phases. The winged helix fold structure of Cdt1_m is similar to the structures of Cdt1_c and other archaeal homologues of the eukaryotic replication initiator, without apparent sequence similarity.
Feature 1:Cdt1-Geminin permissive interaction site
Comment:Inhibition of Cdt1 by Geminin is essential to prevent DNA rereplication.
Comment:The Cdt1-Geminin complex can exist in two distinct forms, a permissive heterotrimer and an inhibitory heterohexamer. The transition between the heterotrimer and the heterohexamer has been postulated to represent a molecular switch between licensing-competent and licensing-defective states.
Structure:2WVR; Human Cdt1-geminin permissive heterotrimer interaction at 4.0A - View structure with Cn3D