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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Wollnik, Bernd Lew, Erin D. Bae, Jae Hyun Rohmann, Edyta Schlessinger, Joseph |
| Description | Author Affiliation: Lew ED ( Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.); |
| 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 of the kinase rather than by static crystallographic snapshots of minor structural variations. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 50 |
| Volume Number | 104 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2007-12-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Abnormalities, Multiple Receptor, Fibroblast Growth Factor, Type 2 Chemistry Metabolism Adenosine Triphosphate Alanine Genetics Crystallography, X-Ray Models, Molecular Mutation Phosphorylation Protein Binding Protein Structure, Tertiary Receptor, Fibroblast Growth Factor, Type 1 Antagonists & Inhibitors Structural Homology, Protein Substrate Specificity Syndrome Research Support, N.I.H., Extramural Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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