Dimerization deficiency of enigmatic retinitis pigmentosa-linked rhodopsin mutants

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


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • COS Cells
  • Cattle
  • Chlorocebus aethiops
  • GTP-Binding Proteins / chemistry
  • HEK293 Cells
  • Humans
  • Liposomes / metabolism
  • Mice, Knockout
  • Mutation*
  • Phospholipid Transfer Proteins / metabolism
  • Point Mutation*
  • Protein Multimerization
  • Retina / chemistry
  • Retina / metabolism*
  • Retinitis Pigmentosa / genetics*
  • Rhodopsin / chemistry*
  • Rhodopsin / genetics*
  • Transducin / genetics


  • Liposomes
  • Phospholipid Transfer Proteins
  • Rhodopsin
  • GTP-Binding Proteins
  • Transducin