Activation and inhibition of the C-terminal kinase domain of p90 ribosomal S6 kinases.

ABSTRACT: The p90 ribosomal S6 kinases (RSKs) contain two distinct catalytic kinase domains, the N-terminal and C-terminal kinase domains (NTKD and CTKD, respectively). The activation of CTKD is regulated by phosphorylation by extracellular signal-regulated kinase (ERK1/2) and an autoinhibitory αL helix. Through a mutational series in vitro of the RSK CTKDs, we found a complex mechanism lifting autoinhibition that led us to design constitutively active RSK CTKDs. These are based on a phosphomimetic mutation and a C-terminal truncation (e.g., RSK2 T577E D694*) where a high activity in absence of ERK phosphorylation is obtained. Using these constructs, we characterize IC₅₀ values of ATP-competitive inhibitors and provide a setup for determining specificity constants (k_inact/K

SUBMITTER: Fruergaard MU 

PROVIDER: S-EPMC9941302 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature