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Nat Commun. 2016 Oct 3;7:12832. doi: 10.1038/ncomms12832.

Dimerization deficiency of enigmatic retinitis pigmentosa-linked rhodopsin mutants.

Author information

1
Department of Biochemistry, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA.
2
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
3
Department of Ophthalmology, Duke University Medical Center, Durham, North Carolina 27710, USA.
4
Department of Biological Sciences, Center for Cancer, Genetic Diseases and Gene Regulation, Fordham University, Bronx, New York 10458, USA.
5
Weill Cornell Medicine-Qatar, Qatar Foundation, Education City P.O.Box 24144, Doha, State of Qatar.
6
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
7
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8.

Abstract

Retinitis pigmentosa (RP) is a blinding disease often associated with mutations in rhodopsin, a light-sensing G protein-coupled receptor and phospholipid scramblase. Most RP-associated mutations affect rhodopsin's activity or transport to disc membranes. Intriguingly, some mutations produce apparently normal rhodopsins that nevertheless cause disease. Here we show that three such enigmatic mutations-F45L, V209M and F220C-yield fully functional visual pigments that bind the 11-cis retinal chromophore, activate the G protein transducin, traffic to the light-sensitive photoreceptor compartment and scramble phospholipids. However, tests of scramblase activity show that unlike wild-type rhodopsin that functionally reconstitutes into liposomes as dimers or multimers, F45L, V209M and F220C rhodopsins behave as monomers. This result was confirmed in pull-down experiments. Our data suggest that the photoreceptor pathology associated with expression of these enigmatic RP-associated pigments arises from their unexpected inability to dimerize via transmembrane helices 1 and 5.

PMID:
27694816
PMCID:
PMC5059438
DOI:
10.1038/ncomms12832
[Indexed for MEDLINE]
Free PMC Article

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