AI Article Synopsis
- - CDC7 is a crucial Ser/Thr kinase involved in DNA replication during the S phase of the cell cycle, with its activity regulated by DBF4.
- - Crystal structures of CDC7-DBF4 show how a zinc-finger domain stabilizes the kinase's activation loop, facilitating access to the active site for substrate binding.
- - The study reveals how CDC7 selectively phosphorylates specific Ser/Thr residues, providing insights into its activation by DBF4 and the recognition of its preferred substrates.
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416108 | PMC |
| http://dx.doi.org/10.1016/j.str.2020.05.010 | DOI Listing |
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