1.F.1.1.1
The SNARE fusion complex, fusing neurotransmitter vesicles with the presynaptic membrane. Ca²⁺ acts on the synaptic vesicle synaptotagmin1 (synaptotagmin I; SytI, Syt1, SSVP65, SYT) to trigger rapid exocytosis (Chapman, 2008).  Syt1 is a major Ca²⁺ sensor for fast neurotransmitter release. It contains tandem Ca²⁺-binding C2 domains (C2AB), a single transmembrane α-helix and a highly charged 60-residue- long linker in between. The linker region of Syt1 is essential for its two signature functions: Ca²⁺-independent vesicle docking and Ca²⁺-dependent fusion pore opening. The linker contains the basic-amino acid-rich N-terminal region and the acidic amino acid-rich C-terminal region (Lai et al. 2013).  The intrinsically disordered region between Syt I's transmembrane helix and the first C2 domain interats with vesicular lipids and modulates Ca²⁺ binding to C2 (Fealey et al. 2016). t-SNARE and v-SNARE interact in their C-terminal TMSs to promote pore opening (Wu et al. 2016).  Both sides of a trans-SNARE complex can drive pore opening suggesting an indentation model in which multiple SNARE C-termini cooperate in opening the fusion pore by locally deforming the inner leaflets (D'Agostino et al. 2016). The TMSs of SNARE proteins regulate the fusion process (Wu et al. 2017). The cysteine-rich domain of SNAP-23 regulates its membrane association and exocytosis from mast cells (Agarwal et al. 2019). Snc1 is trafficked between the endosomal system and the Golgi apparatus via multiple pathways, providing evidence for protein quality control surveillance of a SNARE protein in the endo-vacuolar system (Ma and Burd 2019). MemDis is a novel prediction method, utilizing a convolutional neural network and long short-term memory networks for predicting disordered regions in transmembrane proteins (Dobson and Tusnády 2021). Curcuminoids (bisdemethoxycurcumin and curcumin) modulate the release of neurotransmitters during exocytosis (Li et al. 2016). Oxidative stress-induced inhibition of VAMP8 trafficking to lysosomes is associated with the development of neurodegenerative diseases due to blocked autophagosome-lysosome fusion (Ohnishi et al. 2022). Calcium (Ca²⁺) plays a critical role in triggering all three primary modes of neurotransmitter release (synchronous, asynchronous, and spontaneous). Synaptotagmin1, a protein with two C2 domains, is the first isoform of the synaptotagmin family that was identified and demonstrated as the primary Ca²⁺ sensor for synchronous neurotransmitter release (Zhou 2023).  Other isoforms of the synaptotagmin family as well as other C2 proteins such as members of the double C2 domain protein family were found to act as Ca²⁺ sensors for different modes of neurotransmitter release. A new model, release-of-inhibition, for the initiation of Ca²⁺-triggered synchronous neurotransmitter release has been proposed. Synaptotagmin1 binds Ca²⁺ via its two C2 domains and relieves a primed pre-fusion machinery. Before Ca²⁺ triggering, synaptotagmin1 interacts Ca²⁺ independently with partially zippered SNARE complexes, the plasma membrane, phospholipids, and other components to form a primed pre-fusion state that is ready for fast release. However, membrane fusion is inhibited until the arrival of Ca²⁺ reorients the Ca²⁺-binding loops of the C2 domain to perturb the lipid bilayers, help bridge the membranes, and/or induce membrane curvatures, which serves as a power stroke to activate fusion (Zhou 2023).  Synaptobrevin2 (Syb2) monomers and dimers differentially engage in regulating the trans-SNARE assembly during membrane fusion. The differential recruitment of two syb2 structures at the membrane fusion site has consequences in regulating individual nascent fusion pore properties. A few syb2 transmembrane domain residues control monomer/dimer conversion. Thus, syb2 monomers and dimers are differentially recruited at the release sites for regulating membrane fusion events (Patil et al. 2024).