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Lock A, Forfar R, Weston C, et al. One motif to bind them: A small-XXX-small motif affects transmembrane domain 1 oligomerization, function, localization, and cross-talk between two yeast GPCRs. Biochim Biophys Acta. 2014;1838(12):3036-51doi: 10.1016/j.bbamem.2014.08.019.
Lock, A., Forfar, R., Weston, C., Bowsher, L., Upton, G. J., Reynolds, C. A., Ladds, G., & Dixon, A. 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, 1838(12), 3036-51. https://doi.org/10.1016/j.bbamem.2014.08.019
Lock, Antonia, et al. "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 vol. 1838,12 (2014): 3036-51. doi: https://doi.org/10.1016/j.bbamem.2014.08.019
Lock A, Forfar R, Weston C, Bowsher L, Upton GJ, Reynolds CA, Ladds G, Dixon AM. One motif to bind them: A small-XXX-small motif affects transmembrane domain 1 oligomerization, function, localization, and cross-talk between two yeast GPCRs. Biochim Biophys Acta. 2014 Dec;1838(12):3036-51. doi: 10.1016/j.bbamem.2014.08.019. Epub 2014 Aug 23. PMID: 25157670.
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Biochim Biophys Acta. 2014 Dec;1838(12):3036-51. doi: 10.1016/j.bbamem.2014.08.019. Epub 2014 Aug 23.

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

Antonia Lock, Rachel Forfar, Cathryn Weston, Leo Bowsher, Graham J G Upton, Christopher A Reynolds, Graham Ladds, Ann M Dixon

Affiliations

  1. Department of Genetics, Evolution and Environment, University College London, WC1E 6BT London, UK.
  2. Division of Biomedical Cell Biology, Warwick Medical School, Coventry, CV4 7AL, UK.
  3. Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.
  4. School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, UK.
  5. Division of Biomedical Cell Biology, Warwick Medical School, Coventry, CV4 7AL, UK.. Electronic address: [email protected].
  6. Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK. Electronic address: [email protected].

PMID: 25157670 DOI: 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.

Copyright © 2014. Published by Elsevier B.V.

Keywords: Cross-talk; GPCR; Oligomerization; Signaling; TOXCAT; Trafficking

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