X-RAY CRYSTALLOGRAPHIC STUDIES OF RIBOSOMAL S6 KINASE 2 (RSK2)

核糖体 S6 激酶 2 (RSK2) 的 X 射线晶体学研究

• 批准号: 7955191
• 负责人: ZIGANG DONG
• 金额: $ 2.14万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955191
• 关键词: C-terminal; Cell Proliferation; Coffin-Lowry syndrome; Computer Retrieval of Information on Scientific Projects Database; Family; Funding; Gene Mutation; Grant; Growth Factor; Human; Institution; Length; Molecular Biology; Molecular Conformation; Molecular Structure; Nature; Pathway interactions; Phosphotransferases; Positioning Attribute; Protein-Serine-Threonine Kinases; Proteins; Publishing; Reporting; Research; Research Personnel; Resolution; Resources; Roentgen Rays; Source; Stream; Structure; United States National Institutes of Health; cancer cell; response; ribosomal protein S6 kinase 2; scaffold; structural biology

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. The 90-kDa ribosomal S6 kinase 2 (RSK2) is important serine-threonine kinase broadly expressed in response to various growth factors. RSK pathway is a key regulator of cancer cell proliferation. In humans, RSK2 gene mutations are manifested in Coffin-Lowry syndrome characterized by severe psychomotor retardation. Mechanism of activation of RSK2 is still unclear, and many contradictive reports are published. Elucidating the molecular structure of RSK2 is essential for understanding its function. RSK2 belongs to the family of unusual serine-threonine kinases that contain two distinct kinase domains connected by a linker region. First, we focused on the regulatory C-terminal domain of RSK2 (CTD), activation of which resulted in activation of full length protein. Recently we determined the X-Ray structure of the isolated CTD RSK2 at 2.0 ¿ resolution and successfully published it (Nature Structural & Molecular Biology, 2008). The structure revealed a C-terminal autoinhibitory ¿L-helix which was embedded in kinase scaffold and pre-determined kinase inactive conformation. We suggested a mechanism of activation by interaction with up-stream kinase, ERK, which would displace the autoinhibitory helix from its position resulting in the re-arrangement of conserved Glu500 residue.

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。 90 kDa核糖体S6激酶2(RSK2)是一种重要的丝氨酸-苏氨酸激酶，广泛表达于多种生长因子中。RSK通路是癌细胞增殖的关键调控因子。在人类中，RSK2基因突变表现为以严重的精神运动迟缓为特征的Coffin-Lowry综合征。RSK2的激活机制目前还不清楚，也有许多相互矛盾的报道。阐明RSK2的分子结构是理解其功能的基础。RSK2属于一个特殊的丝氨酸-苏氨酸激酶家族，它包含两个不同的激酶结构域，通过连接区连接在一起。首先，我们重点研究了RSK2(CTD)的调控C末端结构域，该结构域的激活导致全长蛋白的激活。最近，我们在2.0？分辨率下测定了分离的CTD RSK2的X射线结构，并成功地发表了它(自然结构和分子生物学，2008)。该结构显示了一个C端自抑制的L螺旋，它嵌入了蛋白激酶支架，并预先确定了该蛋白的非活性构象。我们提出了一种通过与上游激酶ERK相互作用而激活的机制，该机制将自身抑制的螺旋从其位置移位，导致保守的Glu500残基重排。