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


Neuronal exocytosis is mediated by a Ca(2+)-triggered membrane fusion event that joins synaptic vesicles and presynaptic membrane. In this event, synaptotagmin I plays a key role as a Ca(2+) 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 Ca(2+)- 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 Ca(2+)-triggered membrane fusion.

date published: 2014 Sep 02
location identifier: 10.1016/j.bpj.2014.07.041 [doi] S0006-3495(14)00786-3 [pii]
pmc: PMC4156666
entrez date: 2014-09-05
registry mumbers: ['0 (Ions)', '0 (Lipid Bilayers)', '0 (Neurotransmitter Agents)', '0 (Synaptotagmin I)', 'SY7Q814VUP (Calcium)']
publication history status: ['2014/03/18 [received]', '2014/07/15 [revised]', '2014/07/22 [accepted]']
volume: 107
date completed: 2015-09-02
pages: 1156-66
journal: Biophysical journal
affiliation: Department of Physics, Center for the Physics of Living Cells, Beckman Institute, University of Illinois Urbana-Champaign, Urbana, Illinois. Department of Physics, Center for the Physics of Living Cells, Beckman Institute, University of Illinois Urbana-Champaign, Urbana, Illinois. Electronic address: kschulte@ks.uiuc.edu.
language: ['eng']
publication status: ppublish
mesh date: 2015-09-04
origin: PubMed
date created: 2014-09-04
owner: NLM
nlm unique id: 0370626
pmid: 25185551
authors: ['Wu, Zhe', 'Schulten, Klaus']
publication type: ['Journal Article', 'Research Support, N.I.H., Extramural', "Research Support, U.S. Gov't, Non-P.H.S."]
issue: 5
status: MEDLINE
journal title abbreviation: Biophys J
source: Biophys J. 2014 Sep 2;107(5):1156-66. doi: 10.1016/j.bpj.2014.07.041.
mesh terms: ['Calcium/*metabolism', 'Ions/metabolism', 'Lipid Bilayers/metabolism', 'Molecular Dynamics Simulation', 'Neurotransmitter Agents/*metabolism', 'Pressure', 'Protein Structure, Secondary', 'Synaptic Vesicles/physiology', 'Synaptotagmin I/*metabolism']
subset: IM

Reference: .. [Wu+Schulten:2014] Wu, Zhe & Schulten, Klaus (2014). '**Synaptotagmin's role in neurotransmitter release likely involves Ca(2+)-induced conformational transition.**' *Biophysical journal*. 107(5), pp. 1156-66.