Kenneth Lindegaard Madsen

Department of Neuroscience, University of Copenhagen

Title: Amphipathic helices in transmembrane proteins drive endocytosis through association with curved membranes – a novel paradigm for membrane trafficking

Abstract: Lipid membranes separate the ins and outs of cells and proteins traversing the membrane maintain the critical flux of nutrients, metabolites and information across this barrier. Proper localization of these proteins is essential for cellular function and misdirection lead to disease. Consensus holds that sorting and localization of transmembrane proteins is achieved through semi-specific interaction with intracellular scaffold-protein. As an complementary mechanism, we have, using GPCR-class proteins as an example, discovered that membrane proteins themselves, can navigate cellular membranes by reading out its curvature without the relying on a complex network of proteins. To this end, TM proteins employ so-called amphipathic helixes, which are positioned in their intracellular unstructured regions.  We have further characterized these membrane-interacting structural elements throughout the humane proteome as well as their evolutionary origin. Finally, as an example of mining this data, we describe the functional role of newly identified amphipathic helices in synaptic vesicle transporters in localization to the most highly curved membrane compartments we know of, namely synaptic vesicles. We believe, that these finding established a framework for better understanding neuronal trafficking process including ultra-fast endocytosis in neurotransmission as well as cellular entry of viruses and neurotoxin and consequently may point to novel avenues for therapeutic intervention and drug delivery.

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