Dimerization deficiency of enigmatic retinitis pigmentosa-linked rhodopsin mutants

Birgit Ploier, Lydia N. Caro, Takefumi Morizumi, Kalpana Pandey, Jillian N. Pearring, Michael A. Goren, Silvia C. Finnemann, Johannes Graumann, Vadim Y. Arshavsky, Jeremy S. Dittman, Oliver P. Ernst () and Anant K. Menon ()
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Birgit Ploier: Weill Cornell Medical College
Lydia N. Caro: University of Toronto
Takefumi Morizumi: University of Toronto
Kalpana Pandey: Weill Cornell Medical College
Jillian N. Pearring: Duke University Medical Center
Michael A. Goren: Weill Cornell Medical College
Silvia C. Finnemann: Center for Cancer, Genetic Diseases and Gene Regulation, Fordham University
Johannes Graumann: Weill Cornell Medical College
Vadim Y. Arshavsky: Duke University Medical Center
Jeremy S. Dittman: Weill Cornell Medical College
Oliver P. Ernst: University of Toronto
Anant K. Menon: Weill Cornell Medical College

Nature Communications, 2016, vol. 7, issue 1, 1-11

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12832

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