title: New insights into FAK signaling and localization based on detection of a FAT domain folding intermediate.
abstract: Mounting evidence suggests that the focal adhesion targeting (FAT) domain, an antiparallel four-helix bundle, exists in alternative conformations that may modulate phosphorylation, ligand binding, and the subcellular localization of focal adhesion kinase (FAK). In order to characterize the conformational dynamics of the FAT domain, we have developed a novel method for reconstructing the folding pathway of the FAT domain by using discrete molecular dynamics (DMD) simulations, with free energy constraints derived from NMR hydrogen exchange data. The DMD simulations detect a folding intermediate, in which a cooperative unfolding event causes helix 1 to lose helical character while separating from the helix bundle. The conformational dynamic features of helix 1 in the intermediate state of the FAT domain are likely to facilitate Y926 phosphorylation, yet interfere with paxillin binding. The presence of this intermediate state in vivo may promote FAK signaling via the ERK/MAPK pathway and by release of FAK from focal adhesions.
authors.affiliation: Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Richard D S
authors.initials: RD
authors.lastname: Dixon
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Chen
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
authors.forename: Sagar D
authors.initials: SD
authors.lastname: Khare
authors.forename: Kirk C
authors.initials: KC
authors.lastname: Prutzman
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schaller
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Campbell
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
mesh_terms: D051416:Focal Adhesion Protein-Tyrosine Kinases; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011487:Protein Conformation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013696:Temperature
chemical_list: D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases