Conformational Dynamics of the Focal Adhesion Targeting Domain Control Specific Functions of Focal Adhesion Kinase in Cells

Handle URI:
http://hdl.handle.net/10754/556843
Title:
Conformational Dynamics of the Focal Adhesion Targeting Domain Control Specific Functions of Focal Adhesion Kinase in Cells
Authors:
Kadaré, Gress; Gervasi, Nicolas; Brami-Cherrier, Karen; Blockus, Heike; El Messari, Said; Arold, Stefan T. ( 0000-0001-5278-0668 ) ; Girault, Jean-Antoine
Abstract:
Focal adhesion (FA) kinase (FAK) regulates cell survival and motility by transducing signals from membrane receptors. The C-terminal FA targeting (FAT) domain of FAK fulfils multiple functions, including recruitment to FAs through paxillin binding. Phosphorylation of FAT on Tyr925 facilitates FA disassembly and connects to the MAPK pathway through Grb2 association, but requires dissociation of the first helix (H1) of the four-helix bundle of FAT. We investigated the importance of H1 opening in cells by comparing the properties of FAK molecules containing wild-type or mutated FAT with impaired or facilitated H1 openings. These mutations did not alter the activation of FAK, but selectively affected its cellular functions, including self-association, Tyr925 phosphorylation, paxillin binding, and FA targeting and turnover. Phosphorylation of Tyr861, located between the kinase and FAT domains, was also enhanced by the mutation that opened the FAT bundle. Similarly phosphorylation of Ser910 by ERK in response to bombesin was increased by FAT opening. Although FAK molecules with the mutation favoring FAT opening were poorly recruited at FAs, they efficiently restored FA turnover and cell shape in FAK-deficient cells. In contrast, the mutation preventing H1 opening markedly impaired FAK function. Our data support the biological importance of conformational dynamics of the FAT domain and its functional interactions with other parts of the molecule.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division; Computational Bioscience Research Center (CBRC)
Citation:
Conformational Dynamics of the Focal Adhesion Targeting Domain Control Specific Functions of Focal Adhesion Kinase in Cells 2015, 290 (1):478 Journal of Biological Chemistry
Journal:
Journal of Biological Chemistry
Issue Date:
2-Jan-2015
DOI:
10.1074/jbc.M114.593632
PubMed ID:
25391654
PubMed Central ID:
PMC4281750
Type:
Article
ISSN:
0021-9258; 1083-351X
Additional Links:
http://www.jbc.org/lookup/doi/10.1074/jbc.M114.593632
Appears in Collections:
Articles; Computational Bioscience Research Center (CBRC); Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorKadaré, Gressen
dc.contributor.authorGervasi, Nicolasen
dc.contributor.authorBrami-Cherrier, Karenen
dc.contributor.authorBlockus, Heikeen
dc.contributor.authorEl Messari, Saiden
dc.contributor.authorArold, Stefan T.en
dc.contributor.authorGirault, Jean-Antoineen
dc.date.accessioned2015-06-12T06:30:36Zen
dc.date.available2015-06-12T06:30:36Zen
dc.date.issued2015-01-02en
dc.identifier.citationConformational Dynamics of the Focal Adhesion Targeting Domain Control Specific Functions of Focal Adhesion Kinase in Cells 2015, 290 (1):478 Journal of Biological Chemistryen
dc.identifier.issn0021-9258en
dc.identifier.issn1083-351Xen
dc.identifier.pmid25391654en
dc.identifier.doi10.1074/jbc.M114.593632en
dc.identifier.urihttp://hdl.handle.net/10754/556843en
dc.description.abstractFocal adhesion (FA) kinase (FAK) regulates cell survival and motility by transducing signals from membrane receptors. The C-terminal FA targeting (FAT) domain of FAK fulfils multiple functions, including recruitment to FAs through paxillin binding. Phosphorylation of FAT on Tyr925 facilitates FA disassembly and connects to the MAPK pathway through Grb2 association, but requires dissociation of the first helix (H1) of the four-helix bundle of FAT. We investigated the importance of H1 opening in cells by comparing the properties of FAK molecules containing wild-type or mutated FAT with impaired or facilitated H1 openings. These mutations did not alter the activation of FAK, but selectively affected its cellular functions, including self-association, Tyr925 phosphorylation, paxillin binding, and FA targeting and turnover. Phosphorylation of Tyr861, located between the kinase and FAT domains, was also enhanced by the mutation that opened the FAT bundle. Similarly phosphorylation of Ser910 by ERK in response to bombesin was increased by FAT opening. Although FAK molecules with the mutation favoring FAT opening were poorly recruited at FAs, they efficiently restored FA turnover and cell shape in FAK-deficient cells. In contrast, the mutation preventing H1 opening markedly impaired FAK function. Our data support the biological importance of conformational dynamics of the FAT domain and its functional interactions with other parts of the molecule.en
dc.relation.urlhttp://www.jbc.org/lookup/doi/10.1074/jbc.M114.593632en
dc.rightsThis research was originally published in Journal of Biological Chemistry. Kadaré, Gress, Nicolas Gervasi, Karen Brami-Cherrier, Heike Blockus, Said El Messari, Stefan T. Arold, and Jean-Antoine Girault. "Conformational Dynamics of the Focal Adhesion Targeting Domain Control specific functions of focal adhesion kinase in cells." Journal of Biological Chemistry 290, no. 1 (2015): 478-491. © the American Society for Biochemistry and Molecular Biologyen
dc.subjectTyrosine-Protein Kinase (Tyrosine Kinase)en
dc.subjectProtein Structureen
dc.subjectProtein Kinaseen
dc.subjectFocal Adhesionsen
dc.subjectConformational changeen
dc.titleConformational Dynamics of the Focal Adhesion Targeting Domain Control Specific Functions of Focal Adhesion Kinase in Cellsen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.contributor.departmentComputational Bioscience Research Center (CBRC)en
dc.identifier.journalJournal of Biological Chemistryen
dc.identifier.pmcidPMC4281750en
dc.eprint.versionPost-printen
dc.contributor.institutionINSERM, UMR-S 839, F-75005 Paris, Franceen
dc.contributor.institutionUniversité Pierre & Marie Curie (UPMC), Sorbonne Universités, F-75005 Paris, Franceen
dc.contributor.institutionInstitut du Fer à Moulin, F-75005 Paris, Franceen
dc.contributor.institutionCentre de Biochimie Structurale, CNRS UMR5048, INSERM U1054, Université de Montpellier I & II, Montpellier, Franceen
kaust.authorArold, Stefan T.en

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