The unconventional G-protein cycle of LRRK2 and Roco proteins

Biochem Soc Trans. 2016 Dec 15;44(6):1611-1616. doi: 10.1042/BST20160224.

Abstract

Mutations in the human leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of hereditary Parkinson's disease (PD). LRRK2 belongs to the Roco family of proteins, which are characterized by the presence of a Ras of complex proteins domain (Roc), a C-terminal of Roc domain (COR) and a kinase domain. Despite intensive research, much remains unknown about activity and the effect of PD-associated mutations. Recent biochemical and structural studies suggest that LRRK2 and Roco proteins are noncanonical G-proteins that do not depend on guanine nucleotide exchange factors or GTPase-activating proteins for activation. In this review, we will discuss the unusual G-protein cycle of LRRK2 in the context of the complex intramolecular LRRK2 activation mechanism.

Keywords: G-proteins activated by nucleotide-dependent dimerization (GAD); Parkinson's disease; Roco proteins; leucine-rich repeat kinase 2 (LRRK2).

Publication types

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

MeSH terms

  • GTP-Binding Proteins / metabolism*
  • Guanine Nucleotide Exchange Factors / metabolism
  • Guanosine Diphosphate / metabolism*
  • Guanosine Triphosphate / metabolism*
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
  • Models, Biological
  • Mutation
  • Parkinson Disease / enzymology*
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Phosphorylation

Substances

  • Guanine Nucleotide Exchange Factors
  • Guanosine Diphosphate
  • Guanosine Triphosphate
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • GTP-Binding Proteins