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

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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.