Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases.
Receptor tyrosine kinase (RTK) signaling is tightly regulated by protein allostery within the intracellular tyrosine kinase domains. Yet the molecular determinants of allosteric connectivity in tyrosine kinase domain are incompletely understood. By means of structural (X-ray and NMR) and functional characterization of pathogenic gain-of-function mutations affecting the FGF receptor (FGFR) tyrosine kinase domain, we elucidated a long-distance allosteric network composed of four interconnected sites termed the 'molecular brake', 'DFG latch', 'A-loop plug', and 'αC tether'. The first three sites repress the kinase from adopting an active conformation, whereas the αC tether promotes the active conformation. The skewed design of this four-site allosteric network imposes tight autoinhibition and accounts for the incomplete mimicry of the activated conformation by pathogenic mutations targeting a single site. Based on the structural similarity shared among RTKs, we propose that this allosteric model for FGFR kinases is applicable to other RTKs.
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States.
Huaibin
H
Chen
Department of Chemistry, New York University, New York, United States.
William M
WM
Marsiglia
Department of Chemistry, New York University, New York, United States.
Min-Kyu
MK
Cho
Wenzhou Medical University, Wenzhou, China.
Zhifeng
Z
Huang
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, United States.
Jingjing
J
Deng
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, United States.
Steven P
SP
Blais
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States.
Weiming
W
Gai
New York Structural Biology Center, New York, United States.
Shibani
S
Bhattacharya
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, United States.
Thomas A
TA
Neubert
Department of Chemistry, New York University, New York, United States.
Nathaniel J
NJ
Traaseth
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, United States.
Moosa
0000-0003-2434-9437
M
Mohammadi
D000494:Allosteric Regulation; D018360:Crystallography, X-Ray; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D050505:Mutant Proteins; D051497:Receptor, Fibroblast Growth Factor, Type 2
E. coli; FGF receptor; NMR; biochemistry; biophysics; crystal structure; protein kinase; receptor tyrosine kinase; structural biology