TY - JOUR
T1 - New insights into FAK signaling and localization based on detection of a FAT domain folding intermediate
AU - Dixon, Richard D.S.
AU - Chen, Yiwen
AU - Ding, Feng
AU - Khare, Sagar D.
AU - Prutzman, Kirk C.
AU - Schaller, Michael D.
AU - Campbell, Sharon L.
AU - Dokholyan, Nikolay V.
N1 - Funding Information:
We would like to thank Michelle King for expressing and purifying 15 N-labeled avian FAT domain. We are also grateful to Dr. Ashutosh Tripathy and Dr. Greg Young for their technical assistance. Support for this work was provided by the National Institutes of Health PO1 HL451000-10, the UNC Junior Faculty Development IBM Fund Award, Muscular Dystrophy Association grant MDA3720, Research Grant No. 5-FY03-155 from the March of Dimes Birth Defect Foundation, and the Program in Molecular and Cellular Biophysics at UNC-CH.
PY - 2004/12
Y1 - 2004/12
N2 - 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.
AB - 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.
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U2 - 10.1016/j.str.2004.09.011
DO - 10.1016/j.str.2004.09.011
M3 - Article
C2 - 15576030
AN - SCOPUS:9944258521
SN - 0969-2126
VL - 12
SP - 2161
EP - 2171
JO - Structure
JF - Structure
IS - 12
ER -