Biochemical and functional characterization of the ROC domain of DAPK establishes a new paradigm of GTP regulation in ROCO proteins

Biochem Soc Trans. 2012 Oct;40(5):1052-7. doi: 10.1042/BST20120155.

Abstract

DAPK (death-associated protein kinase) is a newly recognized member of the mammalian family of ROCO proteins, characterized by common ROC (Ras of complex proteins) and COR (C-terminal of ROC) domains. In the present paper, we review our recent work showing that DAPK is functionally a ROCO protein; its ROC domain binds and hydrolyses GTP. Furthermore, GTP binding regulates DAPK catalytic activity in a novel manner by enhancing autophosphorylation on inhibitory Ser308, thereby promoting the kinase 'off' state. This is a novel mechanism for in cis regulation of kinase activity by the distal ROC domain. The functional similarities between DAPK and the Parkinson's disease-associated protein LRRK2 (leucine-rich repeat protein kinase 2), another member of the ROCO family, are also discussed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Apoptosis Regulatory Proteins / chemistry*
  • Apoptosis Regulatory Proteins / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinases / chemistry*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Death-Associated Protein Kinases
  • Guanosine Triphosphate / metabolism*
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Parkinson Disease / metabolism
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins p21(ras) / chemistry
  • Proto-Oncogene Proteins p21(ras) / metabolism

Substances

  • Apoptosis Regulatory Proteins
  • Guanosine Triphosphate
  • Death-Associated Protein Kinases
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein-Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Proto-Oncogene Proteins p21(ras)