The retinitis pigmentosa 2 gene product is a GTPase-activating protein for Arf-like 3.
The retinitis pigmentosa 2 (RP2) gene is responsible for a particular variant of X chromosome-linked eye disease. Previously, RP2 was shown to bind the GTP form of the small G protein Arf-like 3 (Arl3), thus qualifying as an effector. Here we present the Arl3-GppNHp-RP2 complex structure, which shows features resembling complexes with GTPase-activating proteins (GAPs). Biochemical analysis showing a 90,000-fold stimulation of the GTPase reaction together with the structure of an Arl3-GDP-AlF4--RP2 transition state complex showed that RP2 is an efficient GAP for Arl3, with structural features similar to other GAPs. Furthermore, the effect of mutations in patients with retinitis pigmentosa correlated with their effect on catalysis, in particular the mutation of the arginine finger of RP2. The cognate G protein-GAP pair is conserved in yeast as Cin4-Cin2, and the ability of RP2 to act as a GAP can be correlated with its ability to complement a CIN2-deletion phenotype.
Veltel
Stefan
S
Max-Planck-Institut für molekulare Physiologie, Abteilung Strukturelle Biologie, Otto-Hahn-Str. 11, 44227 Dortmund, Germany.
Gasper
Raphael
R
Eisenacher
Elke
E
Wittinghofer
Alfred
A
D020727:ADP-Ribosylation Factors / Q000502:physiology*; D000818:Animals; D002384:Catalysis; D002850:Chromatography, Gel; D004789:Enzyme Activation; D005136:Eye Proteins / Q000502:physiology*; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D019204:GTP-Binding Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D007700:Kinetics; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice
D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C072178:RP2 protein, human; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C490248:Arl3 protein, mouse; D020727:ADP-Ribosylation Factors