Journal of Biological Chemistry
Volume 280, Issue 2, 14 January 2005, Pages 1284-1291
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Molecular Basis of Cell and Developmental Biology
Suppression of Wild-type Rhodopsin Maturation by Mutants Linked to Autosomal Dominant Retinitis Pigmentosa*

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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, detergentinsoluble complex in which the two proteins are in close (<70 Å) 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.

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Present address: Dept. of Pharmaceutics, Amgen, Inc., Thousand Oaks, CA 91320.

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This work was supported by a grant from NIDDK/National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.