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Structural Basis for the Activation and Target Site Specificity of CDC7 Kinase.

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.

SUBMITTER: Dick SD

PROVIDER: S-EPMC7416108 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Structural Basis for the Activation and Target Site Specificity of CDC7 Kinase.

Dick Samual D SD Federico Stefania S Hughes Siobhan M SM Pye Valerie E VE O'Reilly Nicola N Cherepanov Peter P

Structure (London, England : 1993) 20200609 8

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 c ...[more]

PMID: 32521228

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