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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 90 kDa核糖体S6激酶2（RSK 2）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节因子。在人类中，RSK 2基因突变表现为Coffin-Lowry综合征，其特征是严重的精神发育迟滞。RSK 2的激活机制至今仍不清楚，发表了许多相互矛盾的报道。阐明RSK 2的分子结构对于理解其功能至关重要。RSK 2属于不常见的丝氨酸-苏氨酸激酶家族，其含有由接头区连接的两个不同的激酶结构域。首先，我们专注于RSK 2的调节C-末端结构域（CTD），其激活导致全长蛋白的激活。最近，我们确定了分离的CTD RSK 2的X射线结构，分辨率为2.0“，并成功发表了它（Nature Structural & Molecular Biology，2008）。该结构揭示了嵌入激酶支架中的C-末端自抑制性L-螺旋和预定的激酶失活构象。我们提出了一种激活机制，通过与上游激酶ERK相互作用，这将取代自抑制螺旋从其位置，导致保守的Glu 500残基的重排。

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.