Structural basis for the ORC1-Cyclin A association

Autor: Jikui Song, Boxiao Wang
Rok vydání: 2019
Předmět:
Models
Molecular
Cyclin E
Protein Conformation
Cyclin A
Amino Acid Motifs
Biophysics
Origin Recognition Complex
Crystallography
X-Ray
Biochemistry
ORC1
03 medical and health sciences
Cyclin-dependent kinase
Models
2.1 Biological and endogenous factors
Humans
cyclin-inhibitor complex
Aetiology
Other Information and Computing Sciences
Molecular Biology
030304 developmental biology
Cyclin
0303 health sciences
Cyclin binding
Crystallography
Binding Sites
biology
Chemistry
030302 biochemistry & molecular biology
Cyclin-dependent kinase 2
Cyclin-Dependent Kinase 2
Molecular
Computation Theory and Mathematics
Cell cycle
Cell biology
biology.protein
X-Ray
Origin recognition complex
Biochemistry and Cell Biology
Peptides
Protein Structure Reports
cell cycle regulation
Hydrophobic and Hydrophilic Interactions
Protein Binding
Zdroj: Protein Sci
Protein science : a publication of the Protein Society, vol 28, iss 9
ISSN: 1469-896X
Popis: Progression of cell cycle is regulated by sequential expression of cyclins, which associate with distinct cyclin kinases to drive the transition between different cell cycle phases. The complex of Cyclin A with cyclin-dependent kinase 2 (CDK2) controls the DNA replication activity through phosphorylation of a set of chromatin factors, which critically influences the S phase transition. It has been shown that the direct interaction between the Cyclin A-CDK2 complex and origin recognition complex subunit 1 (ORC1) mediates the localization of ORC1 to centrosomes, where ORC1 inhibits cyclin E-mediated centrosome reduplication. However, the molecular basis underlying the specific recognition between ORC1 and cyclins remains elusive. Here we report the crystal structure of Cyclin A-CDK2 complex bound to a peptide derived from ORC1 at 2.54 a resolution. The structure revealed that the ORC1 peptide interacts with a hydrophobic groove, termed cyclin binding groove (CBG), of Cyclin A via a KXL motif. Distinct from other identified CBG-binding sequences, an arginine residue flanking the KXL motif of ORC1 inserts into a neighboring acidic pocket, contributing to the strong ORC1-Cyclin A association. Furthermore, structural and sequence analysis of cyclins reveals divergence on the ORC1-binding sites, which may underpin their differential ORC1-binding activities. This study provides a structural basis of the specific ORC1-cyclins recognition, with implication in development of novel inhibitors against the cyclin/CDK complexes.
Databáze: OpenAIRE
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