Abstracts
Mechanical control of neurotransmission via a disordered domain of an endocytic protein
Presenting author: Agata Witkowska
Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), , Robert-Rössle-Straße 10, 13125 Berlin [DE], witkowska@fmp-berlin.de
Author(s):
Agata Witkowska, Leonie Rommel, Abdelmoneim Eshra, Gaga Kochlamazashvili, Svea Hohensee, Dmytro Puchkov, Tim Berneiser, Narasimha Swamy Telugu, Sebastian Diecke, Max Ruwolt, Fan Liu, Stefan Hallermann, Volker Haucke
Membrane mechanics is increasingly recognized as a critical regulator of membrane remodeling processes, particularly at sites of dynamic vesicle trafficking like the synapse. However, the mechanisms coordinating these processes remain incompletely understood. We demonstrate that dynamic membrane tension fluctuations directly regulate synaptic vesicle cycle dynamics, revealing a novel molecular mechanism. Using a combination of in vitro reconstitution, optical tension measurements in neurons, and neurotransmission characterization, we identified FBP17, an endocytic protein, as a presynaptic membrane tension sensor. We show that its intrinsically disordered domain undergoes a tension-dependent conformational change, triggering endocytosis, a process crucial for high-fidelity neurotransmission. The conformational change drives endocytosis and modulates neurotransmitter release, revealing how membrane tension acts as a signal, triggering protein rearrangements at the lipid-protein interface. Our findings demonstrate that membrane tension is not merely a passive biophysical property, but an active regulator of signaling, dynamically controlling membrane remodeling. We propose that this interfacial protein dynamics, linked to membrane tension, represents one of the fundamental principles governing membrane remodeling events not only at synapses, but also at other sites such as exo-endocytosis in exocrine and endocrine cells or endosomal membrane scission.