Structural basis
for the clamping and Ca2+ activation of SNARE-mediated fusion by synaptotagmin
Synapotagmin-1 (Syt1) interacts with both SNARE proteins and lipid
membranes to synchronize neurotransmitter release to calcium (Ca2+) influx.
Here we report the cryo-electron microscopy structure of the Syt1–SNARE complex
on anionic-lipid containing membranes. Under resting conditions, the Syt1 C2
domains bind the membrane with a magnesium (Mg2+)-mediated partial insertion of
the aliphatic loops, alongside weak interactions with the anionic lipid headgroups.
The C2B domain concurrently interacts the SNARE bundle via the ‘primary’
interface and is positioned between the SNAREpins and the membrane. In this
configuration, Syt1 is projected to sterically delay the complete assembly of
the associated SNAREpins and thus, contribute to clamping fusion. This
Syt1–SNARE organization is disrupted upon Ca2+-influx as Syt1 reorients into
the membrane, likely displacing the attached SNAREpins and reversing the fusion
clamp. We thus conclude that the cation (Mg2+/Ca2+) dependent membrane
interaction is a key determinant of the dual clamp/activator function of
Synaptotagmin-1.
#Neuroscience #Neurology
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