New insights into FAK signaling and localization based on detection of a FAT domain folding intermediate

Richard D S Dixon, Yiwen Chen, Feng Ding, Sagar D. Khare, Kirk C. Prutzman, Michael D. Schaller, Sharon L. Campbell, Nikolay Dokholyan

Research output: Contribution to journalArticle

55 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2161-2171
Number of pages11
JournalStructure
Volume12
Issue number12
DOIs
StatePublished - Dec 1 2004

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Focal Adhesion Protein-Tyrosine Kinases
Focal Adhesions
Molecular Dynamics Simulation
Phosphorylation
Paxillin
MAP Kinase Signaling System
Hydrogen
Ligands

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Structural Biology

Cite this

Dixon, Richard D S ; Chen, Yiwen ; Ding, Feng ; Khare, Sagar D. ; Prutzman, Kirk C. ; Schaller, Michael D. ; Campbell, Sharon L. ; Dokholyan, Nikolay. / New insights into FAK signaling and localization based on detection of a FAT domain folding intermediate. In: Structure. 2004 ; Vol. 12, No. 12. pp. 2161-2171.
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Dixon, RDS, Chen, Y, Ding, F, Khare, SD, Prutzman, KC, Schaller, MD, Campbell, SL & Dokholyan, N 2004, 'New insights into FAK signaling and localization based on detection of a FAT domain folding intermediate', Structure, vol. 12, no. 12, pp. 2161-2171. https://doi.org/10.1016/j.str.2004.09.011

New insights into FAK signaling and localization based on detection of a FAT domain folding intermediate. / Dixon, Richard D S; Chen, Yiwen; Ding, Feng; Khare, Sagar D.; Prutzman, Kirk C.; Schaller, Michael D.; Campbell, Sharon L.; Dokholyan, Nikolay.

In: Structure, Vol. 12, No. 12, 01.12.2004, p. 2161-2171.

Research output: Contribution to journalArticle

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