This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Receptor tyrosine kinases are involved in diverse processes including cell proliferation, differentiation, migration, wound healing, neurite outgrowth, and cell-cell communication. Fibroblast growth factor receptors (FGFR), in particular, have been implicated in multiple human skeletal dysplasias including dwarfing chondroplasias and craniosynostosis syndromes. Recently, mutations in FGFR2 kinase domain were discovered, which result in Lacrimo-auriculo-dento-digital (LADD) syndrome. This disease is characterized by abnormalities in the lacrimal and salivary glands and malformation of the ears, teeth, and digits. One mutation, A628T, resides in the catalytic core, the site of phosphotransfer, and two others, A648T and R649del650, reside in the activation loop of the kinase. Biochemical evidence suggests that these mutations are loss of function mutations, and in this project, we aimed to understand the mechanism of this inactivation by obtaining a high resolution crystal structure of FGFR2 kinase domain harboring an A628T point mutation. Insight into the how this mutation affects kinase activity may shed light on how some point mutations cause robost activation while others result in loss of the catalytic activity.
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