Format

Send to

Choose Destination
See comment in PubMed Commons below
Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2711-6. doi: 10.1073/pnas.1417571112. Epub 2015 Feb 17.

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

Author information

  • 1Lendület Protein Interaction Group, Institute of Enzymology, Research Centre for Natural Sciences, and.
  • 2Lendület Protein Interaction Group, Institute of Enzymology, Research Centre for Natural Sciences, and Departments of Biochemistry and.
  • 3Departments of Biochemistry and.
  • 4Institute of Chemistry, Laboratory of Structural Chemistry and Biology, 1117 Budapest, Hungary.
  • 5Genetics, Eötvös Loránd University, 1117 Budapest, Hungary; and.
  • 6MTA-ELTE Molecular Biophysics Research Group, Hungarian Academy of Sciences, 1117 Budapest, Hungary;
  • 7Lendület Protein Interaction Group, Institute of Enzymology, Research Centre for Natural Sciences, and remenyi.attila@ttk.mta.hu.

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.

KEYWORDS:

ERK2; RSK1; protein kinase; signal transduction; structural biology

PMID:
25730857
PMCID:
PMC4352816
DOI:
10.1073/pnas.1417571112
[PubMed - indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Support Center