Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1
| Autor: | Ste P. Muench, Rosemarie E. Gough, Martin J. Humphries, Guillaume Jacquemet, Shimin Le, Miao Yu, Benjamin T. Goult, Jie Yan, Claus Jørgensen, Jonathan D. Humphries, Thomas Zacharchenko, Matthew Jones |
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| Rok vydání: | 2021 |
| Předmět: |
LC-MS/MS
liquid chromatography–tandem MS Talin 0301 basic medicine Cell division CID collision-induced dissociation Amino Acid Motifs Mechanotransduction Cellular environment and public health Biochemistry TIRF total internal reflection fluorescence Mice CDK1 cyclin-dependent kinase-1 Phosphorylation Cytoskeleton 0303 health sciences biology Chemistry 030302 biochemistry & molecular biology Cell cycle IAC integrin adhesion complex ECM extracellular matrix Cell biology adhesion cyclin-dependent kinase cell cycle biological phenomena cell phenomena and immunity Research Article Protein Binding CDK1 integrin Integrin macromolecular substances Models Biological 03 medical and health sciences Protein Domains Cyclin-dependent kinase Cell Line Tumor CDC2 Protein Kinase Cell Adhesion Animals Humans Amino Acid Sequence Cell adhesion Mitosis Molecular Biology QH581.2 mechanotransduction 030304 developmental biology Cyclin-dependent kinase 1 Binding Sites 030102 biochemistry & molecular biology Cell growth Cell Biology Actin cytoskeleton 030104 developmental biology biology.protein PTM posttranslational modification |
| Zdroj: | The Journal of Biological Chemistry Journal of Biological Chemistry |
| ISSN: | 0021-9258 |
| DOI: | 10.1016/j.jbc.2021.100837 |
| Popis: | Talin is a mechanosensitive component of adhesion complexes that directly couples integrins to the actin cytoskeleton. In response to force, talin undergoes switch-like behaviour 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 synchronised phosphorylation of a large number of protein targets. CDK1 activity also maintains adhesion during interphase, and its inhibition is a prerequisite for the tightly choreographed changes in cell shape and adhesiveness that are required for successful completion of 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 through the use of recombinant fragments. Talin also contains a consensus CDK1 phosphorylation motif centred on S1589; a site that was phosphorylated by CDK1in vitro. A phosphomimetic mutant of this site within talin lowered the binding affinity of KANK and weakened the mechanical response of the region, potentially altering downstream mechanotransduction pathways. The direct binding of the master cell cycle regulator, CDK1, to the primary integrin effector, talin, therefore provides a primordial solution for coupling the cell proliferation and cell adhesion machineries, and thereby enables microenvironmental control of cell division in multicellular organisms.SummaryThe direct binding of the master cell cycle regulator, CDK1, to the primary integrin effector, talin, provides a primordial solution for coupling the cell proliferation and cell adhesion machineries, and thereby enables microenvironmental control of cell division. |
| Databáze: | OpenAIRE |
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