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Structural basis for the autoinhibition of human RSK1 C-terminal kinase domain
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The p90 ribosomal S6 kinases (RSKs), downstream effectors of mitogen-activated protein kinase signaling pathway, comprise a family of Ser/Thr kinases involved in the regulation of various cellular processes such as cell growth, proliferation and survival. Human RSKs comprise two non-identical kinase domains. The N-terminal kinase domain of RSK (RSK NTKD) is responsible for phosphorylation of substrates. The C-terminal kinase domain of RSK (RSK CTKD) involves in autophosporylation. The activation of RSK starts with the activation of RSK CTKD by extracellular signal-regulated kinase-1/2 (ERK1/2). The activated RSK CTKD initiates the following phosphorylation precesses and finally activates RSK NTKD. The fully activated RSK is thus able to phosphorylate downstream substrates to modulate diverse cellular processes. The group leaded by Dr. Xiao-Dong Su from Peking University has gained insight into the structure and function of human RSK1 CTKD. Their work has been published in Acta Cryst. (2012). D68, 680-685.

The Su group presented the crystal structure of human RSK1 CTKD at 2.7 Å resolution. They showed that the structure of human RSK1 CTKD is a typical bilobed kinase fold, consisting of a smaller N-terminal lobe and a larger C-terminal lobe. The residues essential for catalysis in the ATP-binding cleft share similar conformations with those in the active forms of kinases, suggesting that the ATP-binding site is ready for phosphotransfer. However, RSK1 adopts a negatively regulatory mechanism, and the CTKD is inactive before binding of the upstream ERK1/2. The Su group reveals an autoinhibition mechaniam of RSK1 CTKD. They found that an extra C-terminal a helix (aL) embedding in a cradle shaped by the aF-aG junction forms a distinct structural feature that sits in the putative substrate-binding groove fixed and orientated by the ionic interactions between E496, D499 and K695, and the hydrogen bonding between S599 and Y702, thus blocks the peptide substrate binding site. In vitro and in vivo studies have shown that truncation or mutation of the putative autoinhibitory a helix in the RSKs results in constitutive activation of RSK CTKD. The structural observation explains mutation of Y702A in the counterpart residue in RSK2 resulted in activation of the CTKD. Meanwhile, they suggest that ERK1/2 may activate RSK1 by phosphorylating RSK1 followed by displacing aL from its inhibitory position.

Structure of human RSK1 CTKD. (a) Superimposition of ATP binding cleft of RSK1 CTKD (cyan) and PKA (orange; PDB code: 1CDK). P-loop in RSK1 CTKD is disordered. The catalytic residues which are required for optimal phosphotransfer are shown in sticks and labeled. (b) Overall structure. The missing regions are indicated by dotted lines. (c) The interactions of the inhibitory aL-helix (pink) with the rest of the structure (cyan).

As a member of RSK family, RSK1 plays an important role in many cellular processes. RSK1 is expressed ubiquitously in almost all human tissues, predominantly in kidney, lung and pancreas. Recent studies have shown that RSK1 is overexpressed in primary breast and prostate cancers, and is possible to be an anticancer target. The atomic structure of human RSK1 CTKD is of great interest for the understanding of RSK activation mechanism and structure-based anticancer drug development. Right after the structure deposited to the PDB, even before publication, this work has drawn world-wide interests from scientists working on kinases. Now the Su group has established collaboration with Dr. Giulio Rastelli from UNIMORE, Italy, on RSK1 inhibitor design. “RSK1 is a potential anti-cancer target and its crystal structure should prove useful for the design of inhibitors, therefore this is a very worthwhile study.” commented by an anonymous reviewer.


Li, D., Fu, T.-M., Nan, J., Liu, C., Li, L.-F., Su, X.-D.  “Structural basis for the autoinhibition of the C-terminal kinase domain of human RSK1”, Acta Crystallogr D Biol Crystallogr., 68(Pt 6):680-5, 2012.

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