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One motif to bind them : a small-XXX-small motif affects transmembrane domain 1 oligomerization, function, localization, and cross-talk between two yeast GPCRs
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Lock, Antonia, Forfar, Rachel, Weston, Cathryn, Bowsher, L, Upton, Graham J.G., Reynolds, Christopher A., Ladds, Graham and Dixon, Ann M. (2014) One motif to bind them : a small-XXX-small motif affects transmembrane domain 1 oligomerization, function, localization, and cross-talk between two yeast GPCRs. Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1838 (Number 12). pp. 3036-3051. doi:10.1016/j.bbamem.2014.08.019
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Official URL: http://dx.doi.org/10.1016/j.bbamem.2014.08.019
Abstract
G protein-coupled receptors (GPCRs) are the largest family of cell-surface receptors in mammals and facilitate a range of physiological responses triggered by a variety of ligands. GPCRs were thought to function as monomers, however it is now accepted that GPCR homo- and hetero-oligomers also exist and influence receptor properties. The Schizosaccharomyces pombe GPCR Mam2 is a pheromone-sensing receptor involved in mating and has previously been shown to form oligomers in vivo. The first transmembrane domain (TMD) of Mam2 contains a small-XXX-small motif, overrepresented in membrane proteins and well-known for promoting helix-helix interactions. An ortholog of Mam2 in Saccharomyces cerevisiae, Ste2, contains an analogous small-XXX-small motif which has been shown to contribute to receptor homo-oligomerization, localization and function. Here we have used experimental and computational techniques to characterize the role of the small-XXX-small motif in function and assembly of Mam2 for the first time. We find that disruption of the motif via mutagenesis leads to reduction of Mam2 TMD1 homo-oligomerization and pheromone-responsive cellular signaling of the full-length protein. It also impairs correct targeting to the plasma membrane. Mutation of the analogous motif in Ste2 yielded similar results, suggesting a conserved mechanism for assembly. Using co-expression of the two fungal receptors in conjunction with computational models, we demonstrate a functional change in G protein specificity and propose that this is brought about through hetero-dimeric interactions of Mam2 with Ste2 via the complementary small-XXX-small motifs. This highlights the potential of these motifs to affect a range of properties that can be investigated in other GPCRs.
| Item Type: | Journal Article | ||||||||||
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| Divisions: | Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology Faculty of Science > Chemistry Faculty of Medicine > Warwick Medical School |
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| Journal or Publication Title: | Biochimica et Biophysica Acta (BBA) - Biomembranes | ||||||||||
| Publisher: | Elsevier BV | ||||||||||
| ISSN: | 0005-2736 | ||||||||||
| Official Date: | December 2014 | ||||||||||
| Dates: |
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| Volume: | Volume 1838 | ||||||||||
| Number: | Number 12 | ||||||||||
| Page Range: | pp. 3036-3051 | ||||||||||
| DOI: | 10.1016/j.bbamem.2014.08.019 | ||||||||||
| Status: | Peer Reviewed | ||||||||||
| Publication Status: | Published | ||||||||||
| Access rights to Published version: | Restricted or Subscription Access |
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