TABLE 1.
Proteins implicated in SG fusion.
| Protein (Hu/mo gene name) | Functional domains | Role in MC exocytosis |
| SNAP-23 = Synaptosomal-associated protein 23 (SNAP23/Snap23) |  |
PM-localized t-SNARE; enhanced trans-SNARE complex formation and cytoplasmic relocation along degranulation channels (SG and SG-PM fusion) in stimulated MC; Inhibition of stimulated exocytosis in KD MC and after introduction of blocking Abs |
| STX3 = Syntaxin 3 (STX3/Stx3) |  |
SG-localized t-SNARE; enhanced trans-SNARE complex formation and PM relocation (SG-SG and SG-PM fusion) in stimulated MC; inhibition of stimulated exocytosis in KO/KD MC |
| STX4 = Syntaxin 4 (STX4/Stx4) |  |
PM-localized t-SNARE; enhanced trans-SNARE complex formation upon stimulation (role in SG-PM fusion?); no inhibition of stimulated exocytosis in KO MC; partial inhibition in KD MC |
| STX11 = Syntaxin 11 (STX11/Stx11) |  |
Expression upregulated upon IgE/Ag and LPS stimulation; no inhibition of stimulated exocytosis in KO MC; plays a role in lytic granule exocytosis in NK and T cells |
| VAMP8 = Vesicle-associated membrane protein-8, also endobrevin (VAMP8/Vamp8) |  |
Endosomal, lysosomal and SG-localized v-SNARE; enhanced trans-SNARE complex formation in stimulated MC (role in SG and SG-PM fusion); partial inhibit of stimulated exocytosis in KO and KD MC; one manuscript reports specific effect on β-hexosaminidase but not histamine secretion |
| VAMP7 = vesicle-associated membrane protein 7, also Tetanus Insensitive Ti-VAMP (VAMP7/Vamp7) |  |
Punctuate staining pattern in resting hu MC (SG?), PM relocation in stimulated primary hu MC; enhanced trans-SNARE complexes upon stimulation in hu MC; inhibition of stimulated exocytosis In KD MC and after introduction of blocking Abs |
| VAMP2 = vesicle associated membrane protein 2, also Synaptobrevin-2 (VAMP2 or SYB2/Vamp2 or Syb2) |  |
Transfected (but not endogenous) fluorescent VAMP2 showed cytoplasmic (SG?) staining; PM translocation in transfected, stimulated RBL cells, enhanced trans-SNARE complexes in stimulated VAMP8 KO but not in WT BMMC; no inhibition of stimulated exocytosis in KO BMMC, inhibition with blocking Abs in RBL but not hu MC |
| SYT2 = Synaptotagmin-2 (SYT2/Syt2) |  |
SG-localized Ca2+ sensor; inhibition of stimulated exocytosis in KO MC |
| CPLX2 = Complexin 2, also Complexin II or Synaphin-1 (CPLX2/Cplx2) |  |
Punctuate cytoplasmic staining; PM translocation in stimulated RBL cells, pulldown assay reveals binding to an assembled STX3 (not STX4)/SNAP-23/VAMP2 or VAMP8 SNARE complex; stimulated exocytosis is inhibited in KD RBL cells, Ca2+ titration experiments show that CPLX2 increases Ca2+ sensitivity |
| Munc13-4 = mammalian uncoordinated protein 13-4, also protein unc-13 homolog D (UNC13D/unc13d) |  |
Interacts with SG localized Rab27a or b? through a non-canonical motif, the Rab27/Munc13-4 complex is necessary to dock SG at the PM; substantial inhibition of stimulated exocytosis in KO MC; in neuronal cells Munc13 homologues promote disassembly of the closed Munc18/STX complex; assures together with Munc18 proper parallel SNARE zippering |
| DOC2α = Double C2-like domain-containing protein alpha (DOC2A/Doc2a) |  |
Interacts with Munc13-4 on SG via N-terminal MID and C-terminal C2B domain, colocalizes with SG, partial inhibition of stimulated exocytosis in KD and KO MC |
| Munc18-2/Munc18b = mammalian uncoordinated protein 18-2/18b, also syntaxin binding protein 2 (STXBP2) or protein unc-18 homolog 2/b (STXBP2/Stxbp2) |  |
Interacts with SG-localized STX3, Munc18 has two binding modes: binding in closed conformation to a STX SNARE blocks SNARE zippering; binding in an open conformation to STX SNARE (implicating N-terminal peptide) enables zippering; assures together with Munc13-4 proper parallel SNARE zippering |
| SCAMP2 = Secretory carrier-associated membrane protein 2 (SCAMP2/Scamp2) |  |
A tetraspanin that may participate in organizing the phospholipid composition for fusion pore formation by coupling Arf6-stimulated PLD generating PIP2; implicates a peptide (E-peptide) as its expression inhibits stimulated exocytosis in MC |
| STXBP5 = Syntaxin binding protein 5 or tomosyn-1 or Lethal(2) giant larvae protein homolog 3 (STXBP5/Stxbp5) |  |
Binds to STX3 and STX4; acts as a fusion clamp as stimulated exocytosis is enhanced in KD MC; STX4 binding decreases and STX3 increases after stimulation in MC; STXBP5 becomes phosphorylated on multiple S/T residues during stimulation promoting STX3 association and STX4 dissociation |
| Rab3D = Ras-related protein Rab3D (RAB3D/Rab3d) |  |
SG-localized; transient PM relocation upon stimulation; “GTP-bound” mutant inhibits exocytosis; no effect in KO MC (compensatory mechanism?); role in actin coating of SG? |
| RAB5 = Ras-related protein Rab5 (RAB5/rab5) |  |
Role in SG maturation mediating SG fusion during biogenesis; role in stimulated exocytosis favoring SG recruitment of SNAP-23 and SG-SG fusion; In KD MC balance is shifted from compound to full exocytosis with SG-PM fusion only |
| RAB27A = Ras-related protein Rab27A (RAB27A/Rab27a) |  |
SG-localized; regulates cortical actin integrity; switches SG from microtubule-dependent movement to F-actin-dependent docking; enhanced stimulated exocytosis in KO MC; but facilitates stimulated exocytosis together with Rab27b and Munc13-4 (Rab27a magnifies inhibitory effect of Rab27b on stimulated exocytosis in DKO MC) |
| RAB27B = Ras-related protein Rab27B (RAB27B/Rab27b) |  |
SG-localized; regulates microtubule-dependent movement of SG connecting via Slp3 to the kinesin-1 motor; inhibition of stimulated exocytosis in KO MC, may act partly together with Rab27a as inhibition of stimulated exocytosis is magnified in DKO MC |
| RAB37 = Ras-related protein Rab37 (RAB37/Rab37) |  |
SG-localized, GTP-bound Rab37 interacts with Munc13-4 in a trimeric complex containing Rab27 and Munc13-4; KD MC and transfected GTP-bound Rab37 exhibit hypersecretory phenotypes; Rab37 may counteract the Rab27/Munc13-4-dependent docking/priming step |