Understanding Periperal Membrane Protein Interactions | BPS Thematic Meeting

Understanding Peripheral Membrane Protein Interactions: Structure, Dynamics, Function and Therapy

Poster Abstracts

23-POS Board 23 MECHANICAL CONTROL OF NEUROTRANSMISSION VIA A DISORDERED DOMAIN OF AN ENDOCYTIC PROTEIN Agata Witkowska 1,2 ; 1 Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Berlin, Germany 2 NeuroCure Cluster of Excellence, Berlin, Germany Membrane tension 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 of synaptic exo/endocytosis, optical tension measurements in neurons, and advanced 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 and suppressing spontaneous exocytosis – a process crucial for high-fidelity neurotransmission. This biomolecular condensation-to-ordered-assembly transition links exocytosis to rapid, local endocytosis, ensuring synaptic integrity. This conformational change drives localized 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 membrane remodeling sites including exo-endocytosis in exocrine and endocrine cells, immunological synapse formation, and endosomal membrane scission. Understanding these fundamental principles of membrane tension sensing is crucial for elucidating the molecular basis of membrane dynamics and developing therapeutic strategies targeting membrane-associated diseases.

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