Structural and functional impairment of endocytic pathways by retinitis pigmentosa mutant rhodopsin-arrestin complexes.
Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous degenerative eye disease. Mutations at Arg135 of rhodopsin are associated with a severe form of autosomal dominant RP. This report presents evidence that Arg135 mutant rhodopsins (e.g., R135L, R135G, and R135W) are hyperphosphorylated and bind with high affinity to visual arrestin. Mutant rhodopsin recruits the cytosolic arrestin to the plasma membrane, and the rhodopsin-arrestin complex is internalized into the endocytic pathway. Furthermore, the rhodopsin-arrestin complexes alter the morphology of endosomal compartments and severely damage receptor-mediated endocytic functions. The biochemical and cellular defects of Arg135 mutant rhodopsins are distinct from those previously described for class I and class II RP mutations, and, hence, we propose that they be named class III. Impaired endocytic activity may underlie the pathogenesis of RP caused by class III rhodopsin mutations.
Chuang
Jen-Zen
JZ
Department of Ophthalmology, The Margaret M. Dyson Research Institute, New York, NY 10021, USA.
Vega
Carrie
C
Jun
Wenjin
W
Sung
Ching-Hwa
CH
D019943:Amino Acid Substitution; D019393:Arrestin / Q000235:genetics*; D002460:Cell Line; D002478:Cells, Cultured; D004705:Endocytosis / Q000235:genetics*; D006801:Humans; D007668:Kidney; D020125:Mutation, Missense; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000378:metabolism; D012174:Retinitis Pigmentosa / Q000235:genetics*; D012243:Rhodopsin / Q000235:genetics*; D014162:Transfection
D019393:Arrestin; D011994:Recombinant Proteins; D012243:Rhodopsin