Structural Diversity of the Active N-Terminal Kinase Domain of p90 Ribosomal S6 Kinase 2
The p90 ribosomal protein kinase 2 (RSK2) is a highly expressed Ser/Thr kinase activated by growth factors and is involved in cancer cell proliferation and tumor promoter-induced cell transformation. RSK2 possesses two non-identical kinase domains, and the structure of its N-terminal domain (NTD), which is responsible for phosphorylation of a variety of substrates, is unknown. The crystal structure of the NTD RSK2 was determined at 1.8 {angstrom} resolution in complex with AMP-PNP. The N-terminal kinase domain adopted a unique active conformation showing a significant structural diversity of the kinase domain compared to other kinases. The NTD RSK2 possesses a three-stranded {beta}B-sheet inserted in the N-terminal lobe, resulting in displacement of the {alpha}C-helix and disruption of the Lys-Glu interaction, classifying the kinase conformation as inactive. The purified protein was phosphorylated at Ser227 in the T-activation loop and exhibited in vitro kinase activity. A key characteristic is the appearance of a new contact between Lys216 ({beta}B-sheet) and the {beta}-phosphate of AMP-PNP. Mutation of this lysine to alanine impaired both NTDs in vitro and full length RSK2 ex vivo activity, emphasizing the importance of this interaction. Even though the N-terminal lobe undergoes structural re-arrangement, it possesses an intact hydrophobic groove formed between the {alpha}C-helix, the {beta}4-strand, and the {beta}B-sheet junction, which is occupied by the N-terminal tail. The presence of a unique {beta}B-sheet insert in the N-lobe suggests a different type of activation mechanism for RSK2.
- Research Organization:
- Argonne National Laboratory (ANL)
- Sponsoring Organization:
- USDOE
- OSTI ID:
- 1006187
- Journal Information:
- PLoS One, Journal Name: PLoS One Journal Issue: (11) ; 11, 2009 Vol. 4
- Country of Publication:
- United States
- Language:
- ENGLISH
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