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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

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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
Divisions: Faculty of Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology
Faculty of Science > Chemistry
Faculty of Medicine > Warwick Medical School
Journal or Publication Title: Biochimica et Biophysica Acta (BBA) - Biomembranes
Publisher: Elsevier BV
ISSN: 0005-2736
Official Date: December 2014
Dates:
DateEvent
December 2014Published
23 August 2014Available
14 August 2014Accepted
13 February 2014Submitted
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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