8.A.91 The Syntaxin (Syntaxin) Family
Syntaxins, Syxs, play roles in hormone and neurotransmitter exocytosis and are potentially involved in docking of synaptic vesicles at presynaptic active zones. During exocytosis, vesicle-associated v-SNARE (synaptobrevin) and target cell-associated t-SNAREs (syntaxin and SNAP-25) assemble into a core trans-SNARE complex. This complex plays a versatile role at various stages of exocytosis ranging from the priming to fusion pore formation and expansion, finally resulting in the release or exchange of the vesicle content (Han et al. 2017). Syntaxins may also mediate Ca2+-regulation of exocytosis in the acrosomal reaction in sperm (Hutt et al. 2005). SNARE proteins (synaptobrevin, SNAP25 and syntaxin), synaptophysin, Ca2+/calmodulin, and members of the synaptotagmin protein family (Syt1, Syt4, Syt7 and Syt11) are involved in the balance and tight coupling of exo-endocytosis in neurons (Xie et al. 2017). Syntaxins regulate many channels and carriers including those listed in TCDB under TC#s 1.A.1.11.3, 1.A.1.11.4, 1.A.1.11.8, 1.A.1.2.13, 1.A.6.1.1 and 2.A.22.1.4 (see these entries) (Saxena et al. 2006). Some syntaxins are listed under family 1.F.1 (see 1.F.1.1.3 and 1.F.1.1.4). Syntaxin 5 (Stx5) in mammals and its ortholog Sed5p in Saccharomyces cerevisiae mediate anterograde and retrograde endoplasmic reticulum (ER)-Golgi trafficking. The TMSs of syntaxin line the fusion pore of Ca2+-triggered exocytosis, and the fusion pore is formed at least in part by a circular arrangement of 5 to 8 Syx TMSs in the plasma membrane (Han et al. 2004).
.
Syntaxin5, human Stx5 (TC# 8.A.91.1.9) and yeast Sed5p (TC# 8.A.91.1.10), are structurally conserved and are both regulated by interactions with other ER-Golgi SNARE proteins, the Sec1/Munc18-like protein Scfd1/Sly1p and the membrane tethering complexes COG, p115, and GM130. Despite these similarities, yeast Sed5p and mammalian Stx5 are differently recruited to COPII-coated vesicles, and Stx5 interacts with the microtubular cytoskeleton, whereas Sed5p does not. Possibly these different Stx5 interactions contribute to structural differences in ER-Golgi transport between mammalian and yeast cells (Linders et al. 2019).
References:
Syntaxin-related protein, Knolle or Syntaxin111, of 310 aas and 1 C-terminal TMS. Acts as a cell plate-specific syntaxin, required for the fusion of vesicles at the plane of cell division. It is abundant in flowers and developing siliques but is present in low amounts in the seedlings, roots, and leaves. Localizes to the cell plate to mediate cytokinesis (Teh et al. 2013).It and other syntaxins bind Tomosyn to block secretion (Li et al. 2019).
Knolle of Arabidopsis thaliana (Mouse-ear cress)
Syntaxin 5, Sed5, of 340 aas and 1 C-terminal TMS. It is required for vesicular transport between the
endoplasmic reticulum and the Golgi complex (Linders et al. 2019), and acts as an attachment protein receptor (Ghaemmaghami et al. 2003).
Sed5 of Saccharomyces cerevisiae
Syntaxin 17, Stx17, of 302 aas and 2 C-terminal TMSs. It is instrumental for engagement during autophagosome fusion with endolysosomes, and the process is regulated by kinase ULK1 and the apoptosis modulator BRUCE (Viret and Faure 2019). SNAREs localize on opposing membranes and assemble to
form a trans-SNARE complex, an extended, parallel four alpha-helical
bundle that drives membrane fusion (Cheng et al. 2017).
Stx17 of Homo sapiens
Syntaxin 4, Stx4, of 297 aas and one C-terminal TMS. It is a plasma membrane t-SNARE that mediates docking of transport vesicles and is necessary for the translocation of SLC2A4 (glucose transporter; "Glut4, GTR4) from intracellular vesicles to the plasma membrane. Together with STXB3 and VAMP2, it may also play a role in docking/fusion of intracellular GLUT4-containing vesicles with the cell surface in adipocytes and may play a role in docking of synaptic vesicles at presynaptic active zones. Lipid domains assemble syntaxin 4 within themselves by selectively interacting with the transmembrane domain of Stx4. The localized syntaxin 4, in turn, facilitated the fusion of transport vesicles that contained the dopamine transporter with the domain of the plasma membrane, which led to the localized distribution of the transporter to that domain. A pivotal role of a phospholipase A1, specifically PLRP2, is played in the formation of functional domains in the plasma membrane of neurons (Kuge et al. 2020).
Stx4 of Homo sapiens
t-SNARE domain containing proteiin 1, t-SNARE1 of 514 aas and one C-terminal TMS. Schizophrenia-linked protein tSNARE1 regulates endosomal trafficking in cortical neurons (Plooster et al. 2021).
tSNARE1 of Homo sapiens
Syntaxin-22, AtSYP22;AtVAM3; SHOOT GRAVITROPISM 3 protein of 268 aas with 1 C-terminal TMS.
VAM3 of Arabidopsis thaliana (thale cress)
Syntaxin, Stx1b2-prov, of 290 aas and 1 C-terminal TMS.
Stx1b2 of Xenopus laevis (African clawed frog)
Syntaxin 7L, Stx7, of 259 aas and 1 C-terminal TMS.
Stx7 of Xenopus laevis (African clawed frog)
Syntaxin-1A (Stx1; Stx1A; Sx1) of 288 aas. Co-localizes with L-type Ca2+-channels (Cav1.2) in nano clusters at the plasma membrane (Sajman et al. 2017). Munc18 bridges the few syntaxin molecules residing on granules to the syntaxin cluster on the plasma membrane, suggesting that the number of syntaxins on vesicles determines docking and possibly fusion probability (Borisovska 2018). Munc18-1 (P61764; see 1.F.1.1.3)), a neuronal protein that interacts with syntaxin 1 and is required for synaptic vesicle exocytosis, depends on two Munc18-1-interacting proteins called Mint1 or APBA1 (TC# 8.A.24.2.2) and Mint2 or SAPBA2 (TC# 8.A.24.2.3) (Okamoto and Südhof 1997). Syntaxin 1A has a binding site in its H3 domain that is critical for targeting of the H+-ATPase to the apical membrane of renal epithelial cells (Li et al. 2005). The mechanisms regulating syntaxin-1 nanoclustering on the plasma membrane have been considered (Padmanabhan et al. 2019). The syntaxin-1A transmembrane domain has been reconstituted in artificial membranes (Kramer et al. 2022).
Syntaxin 1A of Homo sapiens
Syntaxin homologue, Sso1 of 290 aas and 1 C-terminal TMS (Ghaemmaghami et al. 2003). Membrane fusion transits through hemifusion, a condition in which the outer leaflets of the bilayers are mixed, but the inner leaflets are not. Hemifusion then proceeds to the fusion pore that connects the two internal contents. The TMSs of the fusion proteins play an essential role in the transition from hemifusion to the fusion pore. Sso1p, a target membrane t-SNARE involved in the trafficking from Golgi to plasma membrane. The TMS of Sso1p is a well-defined membrane spanning α-helix. There is an equilibrium between the monomers and the oligomers, and oligomerization is mainly mediated through the interaction at the N-terminal half of the TMS, whereas the C-terminal half is free of the tertiary interaction (Zhang and Shin 2006).
Sso1 of Saccharomyces cerevisiae (Baker's yeast)
Syntaxin 3 (Stx3) of 289 aas with a C-terminal transmembrane anchor domain, is a SNARE protein that is required for its membrane fusion activity. Stx3 also functions as a nuclear regulator of gene expression. Alternative splicing creates a soluble isoform (Stx3S), lacking the transmembrane anchor which binds to the nuclear import factor RanBP5 (RAN-binding protein 5), targets to the nucleus, and interacts physically and functionally with several transcription factors (Giovannone et al. 2018). Mutations can cause microvillus inclusion disease (Julia et al. 2019).
Stx3 of Homo sapiens
Syntaxin-121 of 346 aas and 1 C-terminal TMS. It is a vesicle trafficking protein that functions in the secretory pathway. It is a plasma membrane (PM)-resident syntaxin-like Q-SNARE, that interacts with QUIRKY (QKY; TC# 9.A.57.1.7), a member of the family of multiple C2 domain and transmembrane region proteins (MCTPs), to mediate FLOWERING LOCUS T transport (Liu et al. 2019).
Syp121 of Arabidopsis thaliana (Mouse-ear cress)
Syntaxin-19, Stx19, of 294 aas. S-acylation regulates the trafficking and stability of this unconventional Q-SNARE (Ampah et al. 2018).
Stx19 of Homo sapiens
Syntaxin 5, Stx5, of 355 aas and one C-terminal TMS. It mediates ER to Golgi transport, and together with p115/USO1 and GM130/GOLGA2, is involved in vesicle tethering and fusion at the cis-Golgi membrane to maintain the stacked and inter-connected structure of the Golgi apparatus (Linders et al. 2019). Syntaxin 5 interacts with presenilin holoproteins and affects beta-amyloid peptide production (Suga et al. 2004).
Stx5 of Homo sapiens