The membrane anchor R7BP controls the proteolytic stability of the striatal specific RGS protein, RGS9-2

J Biol Chem. 2007 Feb 16;282(7):4772-4781. doi: 10.1074/jbc.M610518200. Epub 2006 Dec 7.


A member of the RGS (regulators of G protein signaling) family, RGS9-2 is a critical regulator of G protein signaling pathways that control locomotion and reward signaling in the brain. RGS9-2 is specifically expressed in striatal neurons where it forms complexes with its newly discovered partner, R7BP (R7 family binding protein). Interaction with R7BP is important for the subcellular targeting of RGS9-2, which in native neurons is found in plasma membrane and its specializations, postsynaptic densities. Here we report that R7BP plays an additional important role in determining proteolytic stability of RGS9-2. We have found that co-expression with R7BP dramatically elevates the levels of RGS9-2 and its constitutive subunit, Gbeta5. Measurement of the RGS9-2 degradation kinetics in cells indicates that R7BP markedly reduces the rate of RGS9-2.Gbeta5 proteolysis. Lentivirus-mediated RNA interference knockdown of the R7BP expression in native striatal neurons results in the corresponding decrease in RGS9-2 protein levels. Analysis of the molecular determinants that mediate R7BP/RGS9-2 binding to result in proteolytic protection have identified that the binding site for R7BP in RGS proteins is formed by pairing of the DEP (Disheveled, EGL-10, Pleckstrin) domain with the R7H (R7 homology), a domain of previously unknown function that interacts with four putative alpha-helices of the R7BP core. These findings provide a mechanism for the regulation of the RGS9 protein stability in the striatal neurons.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Brain / cytology
  • Brain / physiology
  • Cell Line
  • Dishevelled Proteins
  • GTP-Binding Proteins
  • Gene Expression
  • Humans
  • Mice
  • Neurons / cytology
  • Neurons / physiology*
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • RGS Proteins / genetics
  • RGS Proteins / metabolism*
  • RNA Interference
  • Signal Transduction / physiology*


  • Adaptor Proteins, Signal Transducing
  • Dishevelled Proteins
  • Phosphoproteins
  • R7BP protein, mouse
  • RGS Proteins
  • regulator of g-protein signaling 9
  • GTP-Binding Proteins