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Human cyclin-dependent kinase 2-associated protein 1 (CDK2AP1) is dimeric in its disulfide-reduced state, with natively disordered N-terminal region.

ABSTRACT: CDK2AP1 (cyclin-dependent kinase 2-associated protein 1), corresponding to the gene doc-1 (deleted in oral cancer 1), is a tumor suppressor protein. The doc-1 gene is absent or down-regulated in hamster oral cancer cells and in many other cancer cell types. The ubiquitously expressed CDK2AP1 protein is the only known specific inhibitor of CDK2, making it an important component of cell cycle regulation during G(1)-to-S phase transition. Here, we report the solution structure of CDK2AP1 by combined methods of solution state NMR and amide hydrogen/deuterium exchange measurements with mass spectrometry. The homodimeric structure of CDK2AP1 includes an intrinsically disordered 60-residue N-terminal region and a four-helix bundle dimeric structure with reduced Cys-105 in the C-terminal region. The Cys-105 residues are, however, poised for disulfide bond formation. CDK2AP1 is phosphorylated at a conserved Ser-46 site in the N-terminal "intrinsically disordered" region by I?B kinase ?.

SUBMITTER: Ertekin A

PROVIDER: S-EPMC3351331 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Human cyclin-dependent kinase 2-associated protein 1 (CDK2AP1) is dimeric in its disulfide-reduced state, with natively disordered N-terminal region.

Ertekin Asli A Aramini James M JM Rossi Paolo P Leonard Paul G PG Janjua Haleema H Xiao Rong R Maglaqui Melissa M Lee Hsiau-Wei HW Prestegard James H JH Montelione Gaetano T GT

The Journal of biological chemistry 20120314 20

CDK2AP1 (cyclin-dependent kinase 2-associated protein 1), corresponding to the gene doc-1 (deleted in oral cancer 1), is a tumor suppressor protein. The doc-1 gene is absent or down-regulated in hamster oral cancer cells and in many other cancer cell types. The ubiquitously expressed CDK2AP1 protein is the only known specific inhibitor of CDK2, making it an important component of cell cycle regulation during G(1)-to-S phase transition. Here, we report the solution structure of CDK2AP1 by combine ...[more]

PMID: 22427660

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Project description:Gram-positive pathogenic bacteria Staphylococcus express and secret staphylococcal peroxidase inhibitor (SPIN) proteins to help evade neutrophil-mediated immunity by inhibiting the activity of the main oxidative-defense player myeloperoxidase (MPO) enzyme. SPIN contains a structured 3-helix bundle C-terminal domain, which can specifically bind to MPO with high affinity, and an intrinsically disordered N-terminal domain (NTD), which folds into a structured β-hairpin and inserts itself into the active site of MPO for inhibition. Mechanistic insights of the coupled folding and binding process are needed in order to better understand how residual structures and/or conformational flexibility of NTD contribute to the different strengths of inhibition of SPIN homologs. In this work, we applied atomistic molecular dynamics simulations on two SPIN homologs, from S. aureus and S. delphini, respectively, which share high sequence identity and similarity, to explore the possible mechanistic basis for their different inhibition efficacies on human MPO. Direct simulations of the unfolding and unbinding processes at 450 K reveal that these two SPIN/MPO complexes systems follow surprisingly different mechanisms of coupled binding and folding. While coupled binding and folding of SPIN-aureus NTD is highly cooperative, SPIN-delphini NTD appears to mainly utilize a conformational selection-like mechanism. These observations are in contrast to an overwhelming prevalence of induced folding-like mechanisms for intrinsically disordered proteins that fold into helical structures upon binding. Further simulations of unbound SPIN NTDs at room temperature reveal that SPIN-delphini NTD has a much stronger propensity of forming β-hairpin like structures, consistent with its preference to fold and then bind. These may help explain why the inhibition strength is not well correlated with binding affinity for different SPIN homologs. Altogether, our work establishes the relationship between the residual conformational stability of SPIN-NTD and their inhibitory function, which can help us develop new strategies towards treating Staphylococcal infections. Graphical Abstract

Dataset Information

Human cyclin-dependent kinase 2-associated protein 1 (CDK2AP1) is dimeric in its disulfide-reduced state, with natively disordered N-terminal region.

Publications

Human cyclin-dependent kinase 2-associated protein 1 (CDK2AP1) is dimeric in its disulfide-reduced state, with natively disordered N-terminal region.

Similar Datasets

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