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Conformational dynamics of the focal adhesion targeting domain control specific functions of focal adhesion kinase in

Gress Kadaré1, Nicolas Gervasi1, Karen Brami-Cherrier1

  • 1From the INSERM, UMR-S 839, F-75005 Paris, France, the Université Pierre & Marie Curie (UPMC), Sorbonne Universités, F-75005 Paris, France, the Institut du Fer à Moulin, F-75005 Paris, France.

The Journal of Biological Chemistry
|November 14, 2014
PubMed

Insights

Focal adhesion kinase (FAK) conformational dynamics are crucial for cell survival and motility. Altering the FAT domain

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Focal adhesion kinase (FAK) is a key regulator of cell survival and motility.
  • The C-terminal FA targeting (FAT) domain of FAK mediates recruitment to focal adhesions (FAs) via paxillin binding.
  • Phosphorylation of FAK on Tyr(925) and its association with Grb2 are critical for FA disassembly, requiring the opening of the FAT domain's first helix (H1).

Purpose of the Study:

  • To investigate the functional significance of H1 opening within the FAK FAT domain.
  • To compare the cellular functions of FAK with wild-type FAT domain versus mutated FAT domains exhibiting impaired or facilitated H1 opening.

Main Methods:

  • Utilized FAK molecules with wild-type and mutated FAT domains (impaired/facilitated H1 opening).
  • Assessed FAK activation, self-association, Tyr(925) and Tyr(861) phosphorylation, paxillin binding, and FA targeting/turnover.
  • Evaluated FAK function in FAK-deficient cells.

Main Results:

  • Mutations affecting H1 opening did not alter FAK activation but selectively impacted its cellular functions.
  • Facilitated H1 opening enhanced Tyr(861) and Ser(910) phosphorylation.
  • While mutations favoring H1 opening reduced FA recruitment, they efficiently restored FA turnover and cell shape in FAK-deficient cells.
  • Conversely, mutations preventing H1 opening significantly impaired FAK function.

Conclusions:

  • Conformational dynamics of the FAK FAT domain are biologically important.
  • H1 opening within the FAT domain plays a critical role in regulating FAK's functional interactions and cellular activities.
  • These findings highlight the significance of protein conformational flexibility in signal transduction pathways.
Keywords:
Conformational ChangeFocal AdhesionsProtein KinaseProtein StructureTyrosine-Protein Kinase (Tyrosine Kinase)

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