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, Anant K Menon

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)12832
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 3 Oct 2016
Externally publishedYes

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Retinitis Pigmentosa
Rhodopsin
Dimerization
mutations
dimerization
photoreceptors
Mutation
visual pigments
proteins
Phospholipid Transfer Proteins
Transducin
Retinaldehyde
pathology
compartments
Light
pigments
Retinal Pigments
helices
chromophores
traffic

Cite this

Ploier, B., Caro, L. N., Morizumi, T., Pandey, K., Pearring, J. N., Goren, M. A., ... Menon, A. K. (2016). Dimerization deficiency of enigmatic retinitis pigmentosa-linked rhodopsin mutants. Nature Communications , 7, 12832. https://doi.org/10.1038/ncomms12832

Dimerization deficiency of enigmatic retinitis pigmentosa-linked rhodopsin mutants. / Ploier, Birgit; Caro, Lydia N; Morizumi, Takefumi; Pandey, Kalpana; Pearring, Jillian N; Goren, Michael A; Finnemann, Silvia C; Graumann, Johannes; Arshavsky, Vadim Y; Dittman, Jeremy S; Ernst, Oliver P; Menon, Anant K.

In: Nature Communications , Vol. 7, 03.10.2016, p. 12832.

Research output: Contribution to journalArticleResearchpeer-review

Ploier, B, Caro, LN, Morizumi, T, Pandey, K, Pearring, JN, Goren, MA, Finnemann, SC, Graumann, J, Arshavsky, VY, Dittman, JS, Ernst, OP & Menon, AK 2016, 'Dimerization deficiency of enigmatic retinitis pigmentosa-linked rhodopsin mutants' Nature Communications , vol. 7, pp. 12832. https://doi.org/10.1038/ncomms12832
Ploier B, Caro LN, Morizumi T, Pandey K, Pearring JN, Goren MA et al. Dimerization deficiency of enigmatic retinitis pigmentosa-linked rhodopsin mutants. Nature Communications . 2016 Oct 3;7:12832. https://doi.org/10.1038/ncomms12832
Ploier, Birgit ; Caro, Lydia N ; Morizumi, Takefumi ; Pandey, Kalpana ; Pearring, Jillian N ; Goren, Michael A ; Finnemann, Silvia C ; Graumann, Johannes ; Arshavsky, Vadim Y ; Dittman, Jeremy S ; Ernst, Oliver P ; Menon, Anant K. / Dimerization deficiency of enigmatic retinitis pigmentosa-linked rhodopsin mutants. In: Nature Communications . 2016 ; Vol. 7. pp. 12832.
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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.",
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AB - 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.

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