Structural assembly of the signaling competent ERK2-RSK1 heterodimeric protein kinase complex.
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.
Lendület Protein Interaction Group, Institute of Enzymology, Research Centre for Natural Sciences, and.
Anita
A
Alexa
Lendület Protein Interaction Group, Institute of Enzymology, Research Centre for Natural Sciences, and Departments of Biochemistry and.
Gergő
G
Gógl
Lendület Protein Interaction Group, Institute of Enzymology, Research Centre for Natural Sciences, and.
Gábor
G
Glatz
Departments of Biochemistry and.
Ágnes
Á
Garai
Lendület Protein Interaction Group, Institute of Enzymology, Research Centre for Natural Sciences, and.
András
A
Zeke
Departments of Biochemistry and.
János
J
Varga
Institute of Chemistry, Laboratory of Structural Chemistry and Biology, 1117 Budapest, Hungary.
Erika
E
Dudás
Genetics, Eötvös Loránd University, 1117 Budapest, Hungary; and.
Norbert
N
Jeszenői
Institute of Chemistry, Laboratory of Structural Chemistry and Biology, 1117 Budapest, Hungary.
Andrea
A
Bodor
MTA-ELTE Molecular Biophysics Research Group, Hungarian Academy of Sciences, 1117 Budapest, Hungary;
Csaba
C
Hetényi
Lendület Protein Interaction Group, Institute of Enzymology, Research Centre for Natural Sciences, and remenyi.attila@ttk.mta.hu.
Attila
A
Reményi
D020134:Catalytic Domain; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D009097:Multienzyme Complexes; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1
ERK2; RSK1; protein kinase; signal transduction; structural biology