Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1

Gough, RE, Jones, MC, Zacharchenko, T, Le, S, Yu, M, Jacquemet, G, Muench, SP, Yan, J, Humphries, JD, Jørgensen, C, Humphries, MJ and Goult, BT (2021) Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1. Journal of Biological Chemistry, 297 (1). 100837. ISSN 0021-9258

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Abstract

Talin (TLN1) is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behavior of its multiple rod domains that modulate interactions with its binding partners. Cyclin-dependent kinase-1 (CDK1) is a key regulator of the cell cycle, exerting its effects through synchronized phosphorylation of a large number of protein targets. CDK1 activity maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesion that are required for successful mitosis. Using a combination of biochemical, structural, and cell biological approaches, we demonstrate a direct interaction between talin and CDK1 that occurs at sites of integrin-mediated adhesion. Mutagenesis demonstrated that CDK1 contains a functional talin-binding LD motif, and the binding site within talin was pinpointed to helical bundle R8. Talin also contains a consensus CDK1 phosphorylation motif centered on S1589, a site shown to be phosphorylated by CDK1 in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of the cytoskeletal adaptor KANK and weakened the response of this region to force as measured by single molecule stretching, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator CDK1 to the primary integrin effector talin represents a coupling of cell proliferation and cell adhesion machineries and thereby indicates a mechanism by which the microenvironment can control cell division in multicellular organisms.

Item Type:	Article (Article)
Peer-reviewed:	Yes
Date Deposited:	14 Mar 2022 12:06
Publisher:	American Society for Biochemistry and Molecular Biology
Additional Information:	This is an open access article published in the Journal of Biological Chemistry by American Society for Biochemistry and Molecular Biology.
Divisions:	Faculties > Science and Engineering
Subject terms:	Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, PAXILLIN LD MOTIFS, ACTIN-BINDING, EXTRACELLULAR-MATRIX, INTEGRIN ADHESOME, VINCULIN-BINDING, CELL-DIVISION, RECOGNITION, PROTEIN, PHOSPHORYLATION, TRANSDUCTION, Cell Line, Tumor, Animals, Humans, Mice, CDC2 Protein Kinase, Talin, Cell Adhesion, Mechanotransduction, Cellular, Binding Sites, Amino Acid Sequence, Amino Acid Motifs, Protein Binding, Phosphorylation, Models, Biological, Protein Domains, CDK1, adhesion, cell cycle, cyclin-dependent kinase, integrin, mechanotransduction, talin, Amino Acid Motifs, Amino Acid Sequence, Animals, Binding Sites, CDC2 Protein Kinase, Cell Adhesion, Cell Line, Tumor, Humans, Mechanotransduction, Cellular, Mice, Models, Biological, Phosphorylation, Protein Binding, Protein Domains, Talin, 03 Chemical Sciences, 06 Biological Sciences, 11 Medical and Health Sciences, Biochemistry & Molecular Biology
Data Access Statement:	The atomic coordinates were deposited with the Protein Data Bank, accession code 6TWN. The talin-1-GFP-Trap mass spectrometry proteomics data are given in Table S1 and have been deposited to the ProteomeXchange Consortium via the PRIDE (69) partner repository with the data set identifier PXD024634 and 10.6019/PXD024634. The BirA∗-CDK1 proximity biotinylation mass spectrometry proteomics data are given in Table S2 and have been deposited to the ProteomeXchange Consortium via the PRIDE (69) partner repository with the data set identifier PXD024796 and 10.6019/PXD024796. All other data are contained within the article and the accompanying supporting information.
URI:	https://e-space.mmu.ac.uk/id/eprint/629236
DOI:	https://doi.org/10.1016/j.jbc.2021.100837
ISSN	0021-9258
e-ISSN	1083-351X

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