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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 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、神经突生长和细胞间通讯。 特别是成纤维细胞生长因子受体（FGFR）与多种人类骨骼发育不良有关，包括侏儒软骨发育不良和颅缝早闭综合征。 最近，发现 FGFR2 激酶结构域突变，导致泪-耳-齿-数字 (LADD) 综合征。 这种疾病的特征是泪腺和唾液腺异常以及耳朵、牙齿和手指畸形。 一种突变 A628T 位于催化核心（磷酸转移位点），另外两种突变 A648T 和 R649del650 位于激酶的激活环中。 生化证据表明这些突变是功能丧失突变，在这个项目中，我们旨在通过获得含有 A628T 点突变的 FGFR2 激酶结构域的高分辨率晶体结构来了解这种失活的机制。 深入了解这种突变如何影响激酶活性可能有助于了解某些点突变如何导致机器人激活，而另一些点突变则导致催化活性丧失。