4D4R

Focal Adhesion Kinase catalytic domain

Summary for 4D4R

• Entry DOI: 10.2210/pdb4d4r/pdb
• Related: 4D4S 4D4V 4D4Y 4D55 4D58 4D5H 4D5K
• Descriptor: FOCAL ADHESION KINASE 1, SULFATE ION (3 entities in total)
• Functional Keywords: transferase, kinase inhibitor, atp-binding, integrin signaling
• Biological source: GALLUS GALLUS (CHICKEN)
• Total number of polymer chains: 2
• Total formula weight: 63655.74

Authors

Le Coq, J.,Lin, A.,Lietha, D. (deposition date: 2014-10-31, release date: 2015-02-18, Last modification date: 2023-12-20)

Primary citation

Zhou, J.,Bronowska, A.,Le Coq, J.,Lietha, D.,Grater, F.
Allosteric Regulation of Focal Adhesion Kinase by Pip2 and ATP.
Biophys.J., 108:698-, 2015

PubMed Abstract: Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that regulates cell signaling, proliferation, migration, and development. A major mechanism of regulation of FAK activity is an intramolecular autoinhibitory interaction between two of its domains--the catalytic and FERM domains. Upon cell adhesion to the extracellular matrix, FAK is being translocated toward focal adhesion sites and activated. Interactions of FAK with phosphoinositide phosphatidylinsositol-4,5-bis-phosphate (PIP₂) are required to activate FAK. However, the molecular mechanism of the activation remains poorly understood. Recent fluorescence resonance energy transfer experiments revealed a closure of the FERM-kinase interface upon ATP binding, which is reversed upon additional binding of PIP₂. Here, we addressed the allosteric regulation of FAK by performing all-atom molecular-dynamics simulations of a FAK fragment containing the catalytic and FERM domains, and comparing the dynamics in the absence or presence of ATP and PIP₂. As a major conformational change, we observe a closing and opening motion upon ATP and additional PIP₂ binding, respectively, in good agreement with the fluorescence resonance energy transfer experiments. To reveal how the binding of the regulatory PIP₂ to the FERM F2 lobe is transduced to the very distant F1/N-lobe interface, we employed force distribution analysis. We identified a network of mainly charged residue-residue interactions spanning from the PIP₂ binding site to the distant interface between the kinase and FERM domains, comprising candidate residues for mutagenesis to validate the predicted mechanism of FAK activation.

PubMed: 25650936
DOI: 10.1016/J.BPJ.2014.11.3454

Experimental method

X-RAY DIFFRACTION (1.55 Å)