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Title: Structural Basis for Reduced FGFR2 Activity in LADD Syndrome: Implications for FGFR Autoinhibition and Activation

Abstract

Mutations in fibroblast growth factor receptor 2 (FGFR2) and its ligand, FGF10, are known to cause lacrimo-auriculo-dento-digital (LADD) syndrome. Multiple gain-of-function mutations in FGF receptors have been implicated in a variety of severe skeletal disorders and in many cancers. We aimed to elucidate the mechanism by which a missense mutation in the tyrosine kinase domain of FGFR2, described in the sporadic case of LADD syndrome, leads to reduced tyrosine kinase activity. In this report, we describe the crystal structure of a FGFR2 A628T LADD mutant in complex with a nucleotide analog. We demonstrate that the A628T LADD mutation alters the configuration of key residues in the catalytic pocket that are essential for substrate coordination, resulting in reduced tyrosine kinase activity. Further comparison of the structures of WT FGFR2 and WT FGFR1 kinases revealed that FGFR2 uses a less stringent mode of autoinhibition than FGFR1, which was also manifested in faster in vitro autophosphorylation kinetics. Moreover, the nearly identical conformation of WT FGFR2 kinase and the A628T LADD mutant to either the phosphorylated FGFR2 or FGFR2 harboring pathological activating mutations in the kinase hinge region suggests that FGFR autoinhibition and activation are better explained by changes in the conformational dynamics ofmore » the kinase rather than by static crystallographic snapshots of minor structural variations.« less

Authors:
; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
959488
Report Number(s):
BNL-82474-2009-JA
Journal ID: ISSN 0027-8424; PNASA6; TRN: US201016%%632
DOE Contract Number:
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proceedings of the National Academy of Sciences of the USA; Journal Volume: 104; Journal Issue: 50
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; CONFIGURATION; CRYSTAL STRUCTURE; FIBROBLASTS; GROWTH FACTORS; IN VITRO; KINETICS; MUTANTS; MUTATIONS; NUCLEOTIDES; PHOSPHOTRANSFERASES; RESIDUES; SUBSTRATES; TYROSINE; national synchrotron light source

Citation Formats

Lew,E., Bae, J., Rohmann, E., Wollnik, B., and Schlessinger, J.. Structural Basis for Reduced FGFR2 Activity in LADD Syndrome: Implications for FGFR Autoinhibition and Activation. United States: N. p., 2007. Web. doi:10.1073/pnas.0709905104.
Lew,E., Bae, J., Rohmann, E., Wollnik, B., & Schlessinger, J.. Structural Basis for Reduced FGFR2 Activity in LADD Syndrome: Implications for FGFR Autoinhibition and Activation. United States. doi:10.1073/pnas.0709905104.
Lew,E., Bae, J., Rohmann, E., Wollnik, B., and Schlessinger, J.. Mon . "Structural Basis for Reduced FGFR2 Activity in LADD Syndrome: Implications for FGFR Autoinhibition and Activation". United States. doi:10.1073/pnas.0709905104.
@article{osti_959488,
title = {Structural Basis for Reduced FGFR2 Activity in LADD Syndrome: Implications for FGFR Autoinhibition and Activation},
author = {Lew,E. and Bae, J. and Rohmann, E. and Wollnik, B. and Schlessinger, J.},
abstractNote = {Mutations in fibroblast growth factor receptor 2 (FGFR2) and its ligand, FGF10, are known to cause lacrimo-auriculo-dento-digital (LADD) syndrome. Multiple gain-of-function mutations in FGF receptors have been implicated in a variety of severe skeletal disorders and in many cancers. We aimed to elucidate the mechanism by which a missense mutation in the tyrosine kinase domain of FGFR2, described in the sporadic case of LADD syndrome, leads to reduced tyrosine kinase activity. In this report, we describe the crystal structure of a FGFR2 A628T LADD mutant in complex with a nucleotide analog. We demonstrate that the A628T LADD mutation alters the configuration of key residues in the catalytic pocket that are essential for substrate coordination, resulting in reduced tyrosine kinase activity. Further comparison of the structures of WT FGFR2 and WT FGFR1 kinases revealed that FGFR2 uses a less stringent mode of autoinhibition than FGFR1, which was also manifested in faster in vitro autophosphorylation kinetics. Moreover, the nearly identical conformation of WT FGFR2 kinase and the A628T LADD mutant to either the phosphorylated FGFR2 or FGFR2 harboring pathological activating mutations in the kinase hinge region suggests that FGFR autoinhibition and activation are better explained by changes in the conformational dynamics of the kinase rather than by static crystallographic snapshots of minor structural variations.},
doi = {10.1073/pnas.0709905104},
journal = {Proceedings of the National Academy of Sciences of the USA},
number = 50,
volume = 104,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}