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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 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).


The ten component SNARE fusion complex of Homo sapiens, fusing neurotransmitter vesicles with the presynaptic membrane.

Yeast vacuolar snare complex including the vesicle-associated membrane protein 2 (Snc2p; 115aas; 1-C-terminal TMS) (Chernomordik et al., 2005), the vacuole morphogenesis protein, Vam3 (PTH1) of 283 aas, the vacuolar v-snare, Nyv1 of 253 aas, and the t-snare, Vti1 of 217 aas. Considering these last three proteins, SNARE TMSs serve as non-specific membrane anchors in vacuole fusion, but fusion requires the SNARE complexes in the plasma and vacuolar membranes. Lipid-anchored Vti1 was fully active, lipid-anchored Nyv1 (R-SNARE) permitted the fusion reaction to proceed up to hemifusion, but lipid-anchored Vam3 interfered with fusion before hemifusion. Vam7 (a soluble SNARE; 316 aas) and Sec18 (758 aas) remodel SNARE compexes to allow lipd-anchored R-SNARE (NYV1, 253 aas), acting with Q-SNARE (VTS1; 523 aas), to support vacuole fusion (Jun et al. 2007).Thus, these proteins have non-specific membrane anchors, but each of these proteins makes different contributions to the hemifusion intermediate and opening of the fusion pore (Semenov et al. 2014). The 181-198 region of Qa-snare, immediately upstream of the SNARE heptad-repeat domain, is required for normal fusion activity with HOPS. This region is needed for normal SNARE complex assembly (Song and Wickner 2017). Sec17 and Sec18 act twice in the fusion cycle, binding to trans-SNARE complexes to accelerate fusion, and then to hydrolyze ATP to disassemble cis-SNARE complexes (Song et al. 2017). Fusion with wild-type SNARE domains is controlled by juxtamembrane domains, transmembrane anchors, and Sec17 (Orr et al. 2022).

The vacuolar snare complex of Saccharomyces cerevisiae 

The worm SNARE complex and it's regulators for vesicle neurotransmetter and neuropeptide release (Gracheva et al. 2007).  The core SNARE complex consists of Syntaxin, SNAP and Synaptobrevin and mediates the synaptic vesicle cycle (Rathore et al. 2010).  Synaptotagmin I is a Ca2+ sensor triggering vesicle fusion (Yu et al. 2013).  Regulators include Snapin dimers (Yu et al. 2013), Complexin, a presynaptic protein that interacts with the SNARE complex (the C-terminal domain binds lipids to inhibit exocytosis) (Hobson et al. 2011; Wragg et al. 2013), Unc-18, which binds syntaxin and regluates synaptic vesicle (neurotransmitter) docking (Graham et al. 2011), Unc13 which also regulates docking of the synaptic vesicles to the plasma membrane by interacting with syntaxin, CAPS or Unc31, a Ca2+-activated protein for secretion that is required for dense core vesicle docking for neuropeptide release (Lin et al. 2010), and Tomosyn or Tom-1, a negative regluator of both neurotransmitter and neuropeptide release (Gracheva et al. 2007).

Synaptic vesicle fusion apparatus of Caenorhabditis elegans

The mouse synaptobrevin 2 (syb2)/VAMP2/Syntaxin (Syx)/SNAP-25 complex involved in vesicle fusion pore formation (Chang et al. 2015). The synaptobrevin juxtamembrane regions plus the TMS may catalyze pore formation by forming a membrane-spanning complex that increases curvature stress at the circumference of the hemifused diaphragm of the prepore intermediate state (Tarafdar et al. 2015). The TMS of VAMP2 plays a critical role membrane fusion, and the structural mobility provided by the central small amino acids is crucial for exocytosis by influencing the molecular re-arrangements of the lipid membrane that are necessary for fusion pore opening and expansion (Hastoy et al. 2017). SNARE TMSs may function as parts of the fusion pores during Ca2+-triggered exocytosis for release of both neurotransmitters and hormones (Chiang et al. 2018). The intracellular periodontal pathogen, P. gingivalis, exploits a recycling pathway involving VAMP2 to exit from infected cells (Takeuchi et al. 2016).

Fusion pore forming subunits of Mus musculus
Synaptobrevin-2 (Syb2; Vamp2) of 116 aas and one C-terminal TMS
Syntaxin (SyxB) of 236 aas and one C-terminal TMS
Synaptosomal-associated portein, Snap-25 of 206 aa and 0 TM  

The RABGET1 (RABEX5) - STX6-VAMP3-VTI1B complex mediates fusion between recycling endosomes and Streptococcus (GAS)-containing autophagosome-like vauoles (Nozawa et al. 2017). Macroautophagy/autophagy plays a critical role in immunity by directly degrading invading pathogens such as Group A Streptococcus (GAS), through a process that has been named xenophagy. Autophagic vacuoles directed against GAS, termed GAS-containing autophagosome-like vacuoles (GcAVs), use recycling endosomes (REs) as a membrane source. This complex mediates fusion between GcAVs and REs. STX6 (syntaxin 6) is recruited to GcAVs and forms a complex with VTI1B and VAMP3 to regulate the GcAV-RE fusion that is required for xenophagy. STX6 targets the GcAV membrane through its tyrosine-based sorting motif and transmembrane domain, and localizes to TFRC (transferrin receptor)-positive punctate structures on GcAVs through its H2 SNARE domain. STX6 is required for the fusion between GcAVs and REs to promote clearance of intracellular GAS by autophagy. VAMP3 and VTI1B interact with STX6 which become localized on the TFRC-positive puncta on GcAVs for RE-GcAV fusion. Knockout of RABGEF1 impairs the RE-GcAV fusion and STX6-VAMP3 interaction. Thus, RABGEF1 mediates RE fusion with GcAVs through the STX6-VAMP3-VTI1B complex.

FABGET1 - STX6-VAMP3-VTI1B complex of Homo sapiens
FABGET1 (Q9UJ41) of 708 aas and 0 TMSs
Stx6 (O43752) of 255 aas and 1 C-terminal TMS
VTI1B (Q9UEU0) of 232 aas and 1 C-terminal TMS
VAM3 (VAMP3; Q15836) of 100 aas and 1 C-terminal TMS

Dysferlin/Caveolin 3/MG53 (TRIM72) complex.  Mediates vesicle fusion and membrane repair in muscle cells (Fuson et al. 2014).  Dysferlin (DysF; Fer1L1) belongs to the Ferlin family.  A deficiency of dysferlin, which binds lipids in a Ca2+-dependent process, causes vesicle accumulation near membrane lesions (Roostalu and Strähle 2012). The C2 domains of dysferlin plays roles in membrane localization, Ca2+ signaling and sarcolemmal repair (Muriel et al. 2022). Dysferlin, a transmembrane protein containing 7 C2 domains, C2A through C2G, concentrates in transverse tubules of skeletal muscle, where it stabilizes voltage-induced Ca2+ transients and participates in sarcolemmal membrane repair. Each of dysferlin's C2 domains except C2B regulate Ca(2+) signaling (Muriel et al. 2022).

Dysferlin (DysF; Fer1L1)/Caveolin 3/MG53 (TRIM72) complex of Homo sapiens.
Dysferlin (2080 aas; O75923)
Caveolin 3 (151 aas; P56539)
MG53 (477 aas; Q6ZMU5)  

Myoferlin of 2016 aas and one C-terminal TMS, and possibly another near the N-terminus. It is a calcium/phospholipid-binding protein that plays a role in the plasmalemma repair mechanism of endothelial cells that permits rapid resealing of membranes disrupted by mechanical stress. It is also involved in endocytic recycling.It is also involved in pivotal physiological functions related to numerous cell membranes, such as the endocytosis cycle, vesicle trafficking, membrane repair, membrane receptor recycling, and protein secretion. MYOF is overexpressed in a variety of cancers (Dong et al. 2019; Gu et al. 2020).


Myoferlin of Homo sapiens

Synaptobrevin homolog YKT6 of 198 aas and possibly one N-terminal TMS. It is a vesicular soluble NSF attachment protein receptor (v-SNARE) mediating vesicle docking and fusion to a specific acceptor cellular compartment. It functions in endoplasmic reticulum to Golgi transport, and is part of a SNARE complex composed of GOSR1, GOSR2 and STX5. It functions in early/recycling endosome to TGN transport as part of a SNARE complex composed of BET1L, GOSR1 and STX5 (Tai et al. 2004). It has S-palmitoyl transferase activity and is prenylated (McNew et al. 1997). Double prenylation of Ykt6 is required for lysosomal hydrolase trafficking (Sakata et al. 2021).

Ykt6 of Homo sapiens