GTP binding to the ROC domain of DAP-kinase regulates its function through intramolecular signalling

EMBO Rep. 2011 Sep 1;12(9):917-23. doi: 10.1038/embor.2011.126.

Abstract

Death-associated protein kinase (DAPk) was recently suggested by sequence homology to be a member of the ROCO family of proteins. Here, we show that DAPk has a functional ROC (Ras of complex proteins) domain that mediates homo-oligomerization and GTP binding through a defined P-loop motif. Upon binding to GTP, the ROC domain negatively regulates the catalytic activity of DAPk and its cellular effects. Mechanistically, GTP binding enhances an inhibitory autophosphorylation at a distal site that suppresses kinase activity. This study presents a new mechanism of intramolecular signal transduction, by which GTP binding operates in cis to affect the catalytic activity of a distal domain in the protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Death-Associated Protein Kinases
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • Guanosine Triphosphate / metabolism*
  • HEK293 Cells
  • Humans
  • Oncogene Protein p21(ras) / metabolism
  • Phosphorylation
  • Protein Binding / genetics
  • Protein Multimerization
  • Signal Transduction*

Substances

  • Apoptosis Regulatory Proteins
  • Guanosine Triphosphate
  • Death-Associated Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • GTP-Binding Proteins
  • Oncogene Protein p21(ras)