New evidence to the mechanism of vesicle fusion during neurotransmission

Structural Biology Unit at Molecular Biology Institute of Barcleona (SBU - IBMB - CSIC)

Researchers from the Structural Biology Unit (SBU) provided high resolution snapshots of a protein complex involved in the regulation of synaptic vesicle fusion. Published in the Proceedings of the National Academic of Sciences journal (PNAS), the study sheds new light into the understanding of the neurotransmission mechanism.

Neurons are able to communicate with others through the liberation of neurotransmitters during synapses. Numerous proteins are recruited to the presynaptic space to execute a highly controlled process, resulting in the liberation of neurotransmitters to the synaptic cleft. Many of these proteins share C2 domains as common structural motifs, which are regulated by their binding to Ca2+, phospholipids, or other proteins, endowing them with properties helping to fine-tune the vesicle release mechanisms. Rabphilin-3A (Rph3A) is a membrane trafficking protein involved in the calcium-dependent regulation of secretory vesicle exocytosis in neurons and neuroendocrine cells. However, its exact role in the process still remains under debate.

By the work of the research team of Dr. Nuria Verdaguer and collaborators, the structures of the membrane trafficking protein Rabphilin-3A (Rph3A) C2B domain in complex with other actors of the vesicle fusion process (as protein SNAP25 or the phosphoinositide PIP2 and Ca2+) were solved. The researchers of the “Structural Virology and large Biological Complexes” group discovered a membrane-binding mode in which the Rph3A-C2 domains operate in cooperation with PIP2/Ca2+ and SNAP25 adopting a conformation able to promote membrane bending. This result provides a model to explain how Rph3A regulates various steps of the vesicle fusion process, hence helping better understand signal transmission at the neuronal synapsis.



C. Ferrer-Orta, M.D. Pérez-Sánchez, T. Coronado-Parra, C. Silva, D.López-Martínez, J. Baltanás-Copado, J.C. Gómez-Fernández, S. Corbalán-García, N.Verdaguer. Structural characterization of the Rabphilin-3A-SNAP25 interaction. Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):E5343-E5351.

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