Physical Chemistry Seminar: Professor Dimitrios Stamou, University of Copenhagen

Traditionally, the spatial compartmentalisation of membrane proteins is thought in terms of 2D segregation in plasma membrane (PM) domains enriched in specific lipids. However, the direct observation of such putative domains has been challenging, thus their mechanism of formation remains elusive. Here, 3D imaging of the PM conclusively established the existence of PM domains and revealed a novel general mechanism of 2D spatial organization that is based on energetic coupling of membrane proteins to membrane curvature1-3. Experiments with different families of membrane proteins (including G protein coupled receptors, EGFR, PIEZO1 and H-Ras) revealed this novel mechanism to be general but also protein and protein-conformation specific.4-6

A second ubiquitous type of spatial compartmentalisation is 3D protein segregation in nanoscale organelles. Here we investigated single copies of the proton pumping V-ATPase in single rat-brain synaptic vesicles (SVs)7,8. Our work revealed the V-ATPase does not pump protons continuously in time, consequently SV acidification is stochastic and at any given movement ~50 % of SVs are not acidified8. Such all/none fluctuations in the electrochemical gradient of SVs would by definition regulate in a stochastic manner also proton-coupled secondary active neurotransmitters and neurotransmitter loading to SVs11 and thus play a crucial role in neurotransmission.

(1) Hatzakis, N. S. et al. Nat Chem Biol 2009, 5 (11), 835. (2) Larsen, J. B. et al. Nat Chem Biol 2015, 11 (3), 192. (3) Iversen, L.et al. Nat Chem Biol 2017, 13 (7), 724. (4) Rosholm, K. R.; et al. Nat Chem Biol 2017, 13 (7), 724. (5) Lauritzen, L. et al. results under review. (6) Mathiasen, S. et al. Nat Meth 2014, 11 (9), 931. (7) Veshaguri, S.; et al. Science 2016, 351 (6280), 1469. (8) E. Kosmidis; et al. Nature, in press.