A628T TEV

A628T电视

• 批准号: 7726229
• 负责人: JOSEPH SCHLESSINGER
• 金额: $ 1.19万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-18 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7726229
• 关键词: Affect; Biochemical; Catalytic Domain; Cell Communication; Cell Proliferation; Cells; Computer Retrieval of Information on Scientific Projects Database; Craniosynostosis; Digit structure; Disease; Ear; FGFR2 gene; Fibroblast Growth Factor Receptors; Funding; Grant; Human; Institution; Light; Mutation; Neurites; Phosphotransferases; Point Mutation; Process; Receptor Protein-Tyrosine Kinases; Research; Research Personnel; Resolution; Resources; Salivary Glands; Site; Source; Structure; Syndrome; Tooth structure; United States National Institutes of Health; Wound Healing; digital; insight; lacrimal; loss of function mutation; malformation; migration; skeletal dysplasia

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for 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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 受体酪氨酸激酶参与多种过程，包括细胞增殖、分化、迁移、伤口愈合、突起生长和细胞间通讯。尤其是成纤维细胞生长因子受体(FGFR)，已被认为与多种人类骨骼发育不良有关，包括侏儒性软骨缺乏症和颅突融合综合征。最近，人们发现FGFR2的激动域发生突变，从而导致LAD综合征。这种疾病的特征是泪腺和唾液腺的异常以及耳朵、牙齿和手指的畸形。一个突变A628T位于磷酸化转移的催化核心，另外两个突变A648T和R649del650位于该激酶的激活环中。生化证据表明，这些突变是功能丧失突变，在本项目中，我们旨在通过获得含有A628T点突变的FGFR2激动域的高分辨率晶体结构来了解这种失活的机制。深入了解这种突变是如何影响激酶活性的，可能会揭示一些点突变是如何导致Robost激活，而另一些点突变是如何导致催化活性丧失的。