Allostery governs Cdk2 activation and differential recognition of CDK inhibitors

Abir Majumdar; David J. Burban; Joseph M. Muretta; Andrew R. Thompson; Tiffany A. Engel; Damien M. Rasmussen; Manu V. Subrahmanian; Gianluigi Veglia; David D. Thomas; Nicholas M. Levinson

doi:10.1038/s41589-020-00725-y

Allostery governs Cdk2 activation and differential recognition of CDK inhibitors

Abir Majumdar, David J. Burban, Joseph M. Muretta, Andrew R. Thompson, Tiffany A. Engel, Damien M. Rasmussen, Manu V. Subrahmanian, Gianluigi Veglia, David D. Thomas, Nicholas M. Levinson

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12 Scopus citations

Abstract

Cyclin-dependent kinases (CDKs) are the master regulators of the eukaryotic cell cycle. To become activated, CDKs require both regulatory phosphorylation and binding of a cognate cyclin subunit. We studied the activation process of the G1/S kinase Cdk2 in solution and developed a thermodynamic model that describes the allosteric coupling between regulatory phosphorylation, cyclin binding and inhibitor binding. The results explain why monomeric Cdk2 lacks activity despite sampling an active-like state, reveal that regulatory phosphorylation enhances allosteric coupling with the cyclin subunit and show that this coupling underlies differential recognition of Cdk2 and Cdk4 inhibitors. We identify an allosteric hub that has diverged between Cdk2 and Cdk4 and show that this hub controls the strength of allosteric coupling. The altered allosteric wiring of Cdk4 leads to compromised activity toward generic peptide substrates and comparative specialization toward its primary substrate retinoblastoma (RB).

Original language	English (US)
Pages (from-to)	456-464
Number of pages	9
Journal	Nature Chemical Biology
Volume	17
Issue number	4
DOIs	https://doi.org/10.1038/s41589-020-00725-y
State	Published - Apr 2021

Bibliographical note

Funding Information:
We thank M. Young for the Cdk2 and yeast CAK constructs, J. Endicott for the bovine cyclinA construct and S. Rubin for the RB771–928 construct. We thank J. Dalluge for assistance with mass spectrometry. This work was supported in part by grants from the National Institutes of Health (no. R01 GM121515, N.M.L.) and the National Institutes of Health Cancer Biology Training grant (no. T32 CA009138, A.M.) and Chemistry-Biology Interface Training grant (no. T32 GM132029, D.M.R.).

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© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

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Research Support, N.I.H., Extramural

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title = "Allostery governs Cdk2 activation and differential recognition of CDK inhibitors",

abstract = "Cyclin-dependent kinases (CDKs) are the master regulators of the eukaryotic cell cycle. To become activated, CDKs require both regulatory phosphorylation and binding of a cognate cyclin subunit. We studied the activation process of the G1/S kinase Cdk2 in solution and developed a thermodynamic model that describes the allosteric coupling between regulatory phosphorylation, cyclin binding and inhibitor binding. The results explain why monomeric Cdk2 lacks activity despite sampling an active-like state, reveal that regulatory phosphorylation enhances allosteric coupling with the cyclin subunit and show that this coupling underlies differential recognition of Cdk2 and Cdk4 inhibitors. We identify an allosteric hub that has diverged between Cdk2 and Cdk4 and show that this hub controls the strength of allosteric coupling. The altered allosteric wiring of Cdk4 leads to compromised activity toward generic peptide substrates and comparative specialization toward its primary substrate retinoblastoma (RB).",

author = "Abir Majumdar and Burban, {David J.} and Muretta, {Joseph M.} and Thompson, {Andrew R.} and Engel, {Tiffany A.} and Rasmussen, {Damien M.} and Subrahmanian, {Manu V.} and Gianluigi Veglia and Thomas, {David D.} and Levinson, {Nicholas M.}",

note = "Funding Information: We thank M. Young for the Cdk2 and yeast CAK constructs, J. Endicott for the bovine cyclinA construct and S. Rubin for the RB771–928 construct. We thank J. Dalluge for assistance with mass spectrometry. This work was supported in part by grants from the National Institutes of Health (no. R01 GM121515, N.M.L.) and the National Institutes of Health Cancer Biology Training grant (no. T32 CA009138, A.M.) and Chemistry-Biology Interface Training grant (no. T32 GM132029, D.M.R.). Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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AU - Majumdar, Abir

AU - Burban, David J.

AU - Muretta, Joseph M.

AU - Thompson, Andrew R.

AU - Engel, Tiffany A.

AU - Rasmussen, Damien M.

AU - Subrahmanian, Manu V.

AU - Veglia, Gianluigi

AU - Thomas, David D.

AU - Levinson, Nicholas M.

N1 - Funding Information: We thank M. Young for the Cdk2 and yeast CAK constructs, J. Endicott for the bovine cyclinA construct and S. Rubin for the RB771–928 construct. We thank J. Dalluge for assistance with mass spectrometry. This work was supported in part by grants from the National Institutes of Health (no. R01 GM121515, N.M.L.) and the National Institutes of Health Cancer Biology Training grant (no. T32 CA009138, A.M.) and Chemistry-Biology Interface Training grant (no. T32 GM132029, D.M.R.). Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2021/4

Y1 - 2021/4

N2 - Cyclin-dependent kinases (CDKs) are the master regulators of the eukaryotic cell cycle. To become activated, CDKs require both regulatory phosphorylation and binding of a cognate cyclin subunit. We studied the activation process of the G1/S kinase Cdk2 in solution and developed a thermodynamic model that describes the allosteric coupling between regulatory phosphorylation, cyclin binding and inhibitor binding. The results explain why monomeric Cdk2 lacks activity despite sampling an active-like state, reveal that regulatory phosphorylation enhances allosteric coupling with the cyclin subunit and show that this coupling underlies differential recognition of Cdk2 and Cdk4 inhibitors. We identify an allosteric hub that has diverged between Cdk2 and Cdk4 and show that this hub controls the strength of allosteric coupling. The altered allosteric wiring of Cdk4 leads to compromised activity toward generic peptide substrates and comparative specialization toward its primary substrate retinoblastoma (RB).

AB - Cyclin-dependent kinases (CDKs) are the master regulators of the eukaryotic cell cycle. To become activated, CDKs require both regulatory phosphorylation and binding of a cognate cyclin subunit. We studied the activation process of the G1/S kinase Cdk2 in solution and developed a thermodynamic model that describes the allosteric coupling between regulatory phosphorylation, cyclin binding and inhibitor binding. The results explain why monomeric Cdk2 lacks activity despite sampling an active-like state, reveal that regulatory phosphorylation enhances allosteric coupling with the cyclin subunit and show that this coupling underlies differential recognition of Cdk2 and Cdk4 inhibitors. We identify an allosteric hub that has diverged between Cdk2 and Cdk4 and show that this hub controls the strength of allosteric coupling. The altered allosteric wiring of Cdk4 leads to compromised activity toward generic peptide substrates and comparative specialization toward its primary substrate retinoblastoma (RB).

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Allostery governs Cdk2 activation and differential recognition of CDK inhibitors

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