Synaptotagmin's role in neurotransmitter release likely involves Ca 2+-induced conformational transition

Zhe Wu, Klaus Schulten

Research output: Contribution to journalArticle

Abstract

Neuronal exocytosis is mediated by a Ca2+-triggered membrane fusion event that joins synaptic vesicles and presynaptic membrane. In this event, synaptotagmin I plays a key role as a Ca2+ sensor protein that binds to and bends the presynaptic membrane with its C2B domain, and thereby initiates membrane fusion. We report free energy calculations according to which C2B-induced membrane bending is preceded by a Ca2+- and membrane-dependent conformational transition. In this transition C2B attaches to the membrane, moves its C-terminal helix from the orientation seen in the available (but membrane-free) crystal/NMR structures as pointing away from the membrane (helix-up), to an orientation pointing toward the membrane (helix-down). In the C2B helix-down state, lipid tails in the proximal membrane bilayer leaflet interact with the moved helix and become disordered, whereas tails in the distal leaflet, to keep in contact with the proximal leaflet, become stretched and ordered. The difference in lipid tail packing between the two leaflets results in an imbalance of pressure across the membrane, and thereby causes membrane bending. The lipid-disordering monitored in the simulations is well suited to facilitate Ca2+-triggered membrane fusion.

Original languageEnglish (US)
Pages (from-to)1156-1166
Number of pages11
JournalBiophysical journal
Volume107
Issue number5
DOIs
StatePublished - Sep 2 2014

ASJC Scopus subject areas

  • Biophysics

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