Structural assembly of the signaling competent ERK2-RSK1 heterodimeric protein kinase complex

Proceedings of the National Academy of Sciences of the United States of America
Anita AlexaAttila Reményi

Abstract

Mitogen-activated protein kinases (MAPKs) bind and activate their downstream kinase substrates, MAPK-activated protein kinases (MAPKAPKs). Notably, extracellular signal regulated kinase 2 (ERK2) phosphorylates ribosomal S6 kinase 1 (RSK1), which promotes cellular growth. Here, we determined the crystal structure of an RSK1 construct in complex with its activator kinase. The structure captures the kinase-kinase complex in a precatalytic state where the activation loop of the downstream kinase (RSK1) faces the enzyme's (ERK2) catalytic site. Molecular dynamics simulation was used to show how this heterodimer could shift into a signaling-competent state. This structural analysis combined with biochemical and cellular studies on MAPK→MAPKAPK signaling showed that the interaction between the MAPK binding linear motif (residing in a disordered kinase domain extension) and the ERK2 "docking" groove plays the major role in making an encounter complex. This interaction holds kinase domains proximal as they "readjust," whereas generic kinase domain surface contacts bring them into a catalytically competent state.

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Citations

Jan 19, 2016·Frontiers in Cell and Developmental Biology·Matthias Gaestel
Jul 1, 2015·Proceedings of the National Academy of Sciences of the United States of America·Alan S FutranA James Link
Oct 21, 2016·Cell Reports·Lisa BrenanCory M Johannessen
Oct 31, 2017·The FEBS Journal·Gergő GóglAttila Reményi
Oct 21, 2018·Nature Communications·Jacob Lauwring AndersenPoul Nissen
Jun 14, 2019·Molecular Carcinogenesis·Rachel M SammonsKevin N Dalby
May 7, 2019·IUBMB Life·Susan S TaylorAlexandr P Kornev
Jul 12, 2018·Scientific Reports·Kei OkatsuShuya Fukai
Feb 7, 2019·Journal of Molecular Biology·Gergő GóglLászló Nyitray
Jul 11, 2020·Structure·Péter SokAttila Reményi

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