Structural basis for the activation and target site specificity of CDC7kinase
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
CDC7 is an essential Ser/Thr kinase that acts upon the replicative helicase throughout the S phase of the cell cycle and is activated by DBF4. Here, we present crystal structures of a highly active human CDC7-DBF4 construct. The structures reveal a zinc-finger domain at the end of the kinase insert 2 that pins the CDC7 activation loop to motif M of DBF4 and the C lobe of CDC7. These interactions lead to ordering of the substrate-binding platform and full opening of the kinase active site. In a co-crystal structure with a mimic of MCM2 Ser40 phosphorylation target, the invariant CDC7 residues Arg373 and Arg380 engage phospho-Ser41 at substrate P+1 position, explaining the selectivity of the S-phase kinase for Ser/Thr residues followed by a pre-phosphorylated or an acidic residue. Our results clarify the role of DBF4 in activation of CDC7 and elucidate the structural basis for recognition of its preferred substrates.
Date Issued
2020-08-04
Date Acceptance
2020-05-19
Citation
Structure, 2020, 28 (8), pp.954-962.e4
ISSN
0969-2126
Publisher
Elsevier
Start Page
954
End Page
962.e4
Journal / Book Title
Structure
Volume
28
Issue
8
Copyright Statement
© 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/32521228
PII: S0969-2126(20)30179-9
Subjects
CDC7
DBF4
DDK
XL413
bisubstrate
cell cycle
crystal structure
kinase
kinase inhibitor
zinc-binding domain
Publication Status
Published
Coverage Spatial
United States
Date Publish Online
2020-06-09