Suppression of wild-type rhodopsin maturation by mutants linked to autosomal dominant retinitis pigmentosa.
Autosomal dominant retinitis pigmentosa (ADRP) has been linked to mutations in the gene encoding rhodopsin. Most RP-linked rhodopsin mutants are unable to fold correctly in the endoplasmic reticulum, are degraded by the ubiquitin proteasome system, and are highly prone to forming detergent-insoluble high molecular weight aggregates. Here we have reported that coexpression of folding-deficient, but not folding-proficient, ADRP-linked rhodopsin mutants impairs delivery of the wild-type protein to the plasma membrane. Fluorescence resonance energy transfer and co-precipitation studies revealed that mutant and wild-type rhodopsins form a high molecular weight, detergent-insoluble complex in which the two proteins are in close (<70 A) proximity. Co-expression of ARDP-linked rhodopsin folding-deficient mutants resulted in enhanced proteasome-mediated degradation and steady-state ubiquitination of the wild-type protein. These data suggested a dominant negative effect on conformational maturation that may underlie the dominant inheritance of ARDP.
Rajan
Rahul S
RS
Departments of Chemistry and Biological Sciences, Stanford University, Stanford, California 94305-5430, USA.
Kopito
Ron R
RR
D002460:Cell Line; D005799:Genes, Dominant / Q000235:genetics*; D006031:Glycosylation; D006801:Humans; D009154:Mutation / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D012174:Retinitis Pigmentosa / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D012243:Rhodopsin / Q000235:genetics* / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D025801:Ubiquitin; D012243:Rhodopsin; D046988:Proteasome Endopeptidase Complex