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

Area of Science:

• Neuroscience
• Biophysics
• Molecular Biology

Background:

• Neuronal exocytosis involves Ca(2+)-triggered fusion of synaptic vesicles with the presynaptic membrane.
• Synaptotagmin I acts as a Ca(2+) sensor, initiating membrane fusion through its C2B domain.

Purpose of the Study:

• To investigate the mechanism of Ca(2+)- and membrane-dependent conformational changes in synaptotagmin I's C2B domain.
• To elucidate how these conformational changes lead to membrane bending and facilitate fusion.

Main Methods:

• Free energy calculations were employed to simulate molecular interactions.
• Molecular dynamics simulations were used to analyze conformational transitions and membrane interactions.

Main Results:

• A Ca(2+)- and membrane-dependent conformational transition precedes C2B-induced membrane bending.
• The C2B domain transitions from a helix-up to a helix-down state upon binding to the membrane.
• This transition disorders lipid tails in the proximal leaflet and orders them in the distal leaflet, inducing membrane bending.

Conclusions:

• The conformational transition of synaptotagmin I's C2B domain is crucial for initiating membrane fusion.
• The resulting membrane bending, driven by lipid tail packing differences, facilitates Ca(2+)-triggered exocytosis.