4+4 Defence by Signe Mathiasen – Niels Bohr Institute - University of Copenhagen

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4+4 Defence by Signe Mathiasen

The membrane spanning G-protein coupled receptors, GPCRs, transduce signals across the plasma membrane and facilitate a rich variety of crucial physiological responses. They are believed to form oligomeric states, however the influence of oligomerization on receptor functionality is to date not clear. The plasma membrane lipid bilayer imbedding the receptor is proposed to affect both transmembrane protein function and association. Continuous studies within the field of receptor oligomerization seeking the mechanisms behind such processes have great scientific and pharmalogical impact.

The shape of membrane compartments in cells is highly conserved and extremely curved membranes occur in several biological processes indicating that curvature is an important membrane property. For that reason the topology of cell membranes achieves increasing attention as a potential regulator of numerous vital functions such as protein sorting and localization.

In an effort to investigate GPCR oligomerization and systematically examine the influence of membrane shape on this process we developed a fluorescence-based assay, employing a model membrane system with the prototypical GPCR, human β2-adrenergic receptor, β2AR, reconstituted in lipid vesicles. We monitored receptor oligomerization in membranes of different curvature at the single vesicle level by the use of confocal microscopy.

We found that β2AR forms oligomers and that the oligomer assembly is highly affected by the shape of the membrane. The highly curved membrane only facilitates a monomeric state of the receptor whereas the flat membrane drives β2AR oligomerization, thus we propose that membrane curvature is an allosteric regulator of GPCR assembly.

We envision that the assay could be used to explore the oligomerization of other transmembrane proteins and furthermore serve as a platform for investigating the important interplay between transmembrane protein association and membrane properties varying for example lipid tail length, shape factors etc.

4+4 Defence by Signe Mathiasen