Elucidation of a Four-site Allosteric Network in Fibroblast Growth Factor Receptor Tyrosine Kinases

Overview

Journal Elife

Specialty Biology

Date 2017 Feb 7

PMID 28166054

Citations 25

Authors

Huaibin Chen

William M Marsiglia

Min-Kyu Cho

Zhifeng Huang

Jingjing Deng

Steven P Blais

Weiming Gai

Shibani Bhattacharya

Thomas A Neubert

Nathaniel J Traaseth

Moosa Mohammadi

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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