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The SNARE Machinery in Mast Cell Secretion.

Lorentz A, Baumann A, Vitte J, Blank U - Front Immunol (2012)

Bottom Line: During an allergic response, the high-affinity IgE receptor, FcεRI, becomes cross-linked by receptor-bound IgE and antigen resulting in immediate release of pre-synthesized mediators - stored in granules - as well as in de novo synthesis of various mediators like cytokines and chemokines.Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNARE) proteins were found to play a central role in regulating membrane fusion events during exocytosis.In this review we summarize our current knowledge about the SNARE machinery and its mechanism of action in mast cell secretion.

View Article: PubMed Central - PubMed

Affiliation: Department of Nutritional Medicine, University of Hohenheim Stuttgart, Germany.

ABSTRACT
Mast cells are known as inflammatory cells which exert their functions in allergic and anaphylactic reactions by secretion of numerous inflammatory mediators. During an allergic response, the high-affinity IgE receptor, FcεRI, becomes cross-linked by receptor-bound IgE and antigen resulting in immediate release of pre-synthesized mediators - stored in granules - as well as in de novo synthesis of various mediators like cytokines and chemokines. Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNARE) proteins were found to play a central role in regulating membrane fusion events during exocytosis. In addition, several accessory regulators like Munc13, Munc18, Rab GTPases, secretory carrier membrane proteins, complexins, or synaptotagmins were found to be involved in membrane fusion. In this review we summarize our current knowledge about the SNARE machinery and its mechanism of action in mast cell secretion.

No MeSH data available.


Related in: MedlinePlus

Domain structure of Munc18-1 (A) and Munc13-1 (B) as adapted from Koch et al. (2000); Misura et al. (2000); Li et al. (2011). Numbers above indicate protein or domain boundaries. For Munc18-1 domain boundaries are also directly included in the inset. The Munc18-1 protein contains three domains (with domain 3 being divided in D3a and D3b). According to crystal structure analysis the molecule adopts a horseshoe like structure that holds the STX-bound molecule in its closed conformation. Contact surfaces reside in D1 and D3a, which form the bottom ends of the horseshoe, while D2 and D3b form the upper end. Domain 3b includes the so-called Sly 1 homology domain containing the residue homologous to the Sly1-20 mutant in the yeast Sly1 protein, which bypasses the requirement for a Rab effector protein in yeast vesicular transport (Dascher et al., 1991). Above the domains are also indicated protein kinase C (Ser306 and Ser313) and Cyclin dependent kinase (Thr574) phosphorylation sites that may regulate Munc18-1 effector functions. (B) The Munc13-1 protein contains several calcium-binding C2 domains, a Diacylglycerol (DAG) C1 domain making it responsive to stimulation with PKC as well as a calmodulin binding domain. Note that the ubiquitouisly expressed isoform 13-4, which is important in mast cell exocytosis lacks the N-terminal C2a, CaMb, and C1 domains. The Mun domain shows structural similarity to thethering proteins and may play a role in the transition of the closed conformation of STX molecules by contacting either Munc18 or STX molecules (Li et al., 2011; Sudhof and Rizo, 2011).
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Figure 4: Domain structure of Munc18-1 (A) and Munc13-1 (B) as adapted from Koch et al. (2000); Misura et al. (2000); Li et al. (2011). Numbers above indicate protein or domain boundaries. For Munc18-1 domain boundaries are also directly included in the inset. The Munc18-1 protein contains three domains (with domain 3 being divided in D3a and D3b). According to crystal structure analysis the molecule adopts a horseshoe like structure that holds the STX-bound molecule in its closed conformation. Contact surfaces reside in D1 and D3a, which form the bottom ends of the horseshoe, while D2 and D3b form the upper end. Domain 3b includes the so-called Sly 1 homology domain containing the residue homologous to the Sly1-20 mutant in the yeast Sly1 protein, which bypasses the requirement for a Rab effector protein in yeast vesicular transport (Dascher et al., 1991). Above the domains are also indicated protein kinase C (Ser306 and Ser313) and Cyclin dependent kinase (Thr574) phosphorylation sites that may regulate Munc18-1 effector functions. (B) The Munc13-1 protein contains several calcium-binding C2 domains, a Diacylglycerol (DAG) C1 domain making it responsive to stimulation with PKC as well as a calmodulin binding domain. Note that the ubiquitouisly expressed isoform 13-4, which is important in mast cell exocytosis lacks the N-terminal C2a, CaMb, and C1 domains. The Mun domain shows structural similarity to thethering proteins and may play a role in the transition of the closed conformation of STX molecules by contacting either Munc18 or STX molecules (Li et al., 2011; Sudhof and Rizo, 2011).

Mentions: In contrast to SNARE proteins, less information is available concerning the function of Sec1/Munc18 (SM) proteins known to play fundamental roles in various intracellular secretory trafficking steps (Sudhof and Rothman, 2009). Sec1 mutant yeast cells have been initially identified in a genetic screen in yeast aiming to identify proteins involved in the secretory pathway (Novick et al., 1980). A defect in neurotransmitter release was also apparent for the uncoordinated18 (unc18) ortholog in nematodes (Hosono et al., 1992) and the drosophila Rop protein (Harrison et al., 1994). SM proteins contain seven family members in humans that bind to STX SNAREs (Bock et al., 2001). Three family members are mammalian uncoordinated18 (Munc18) proteins that are more specifically implicated in regulated exocytosis. They include Munc18-1 (sometimes also called Munc18a; Figure 4A), which is largely expressed in neurons and two ubiquitously expressed isoforms Munc18-2 (Munc18b) and Munc18-3 (Munc18c). They show specificity of binding for certain STX family members. Thus, Munc18-1 can interact with STX1, 2, and 3, Munc18-2 with STX1, 3, and slightly with STX2 (Hata and Südhof, 1995); Munc18-3 interacts with STX2 and 4 and to a lesser extent with STX1 (Tellam et al., 1995). Recently, Munc18-2 was also shown to interact with STX11 (Cote et al., 2009). Studies in knock-out mice have clearly underlined the important role of Munc18 proteins in regulated exocytosis. Animals deficient in Munc18-1 have a complete block of neurotransmission and mice die at birth due to a breathing defect (Verhage et al., 2000). Mice deficient in Munc18-3 are early embryonic lethal and in the heterozygous stage are glucose intolerant after receiving high-fat-diet due to a secretion defect in insulin-producing pancreatic beta cells (Oh et al., 2005). On the other hand, externalization of GLUT4 at the cell surface was enhanced in munc18-3 knock-out adipocytes at low concentration of insulin (Kanda et al., 2005). The reported essential role of Munc18 proteins in the secretory pathway was initially difficult to explain as biochemical experiments as well as crystal structure analysis of the STX1/Munc18-1 complex showed that Munc18 binding to their respective STX partners blocked the interaction with other SNAREs rather arguing for a negative regulatory function (Araki et al., 1997; Misura et al., 2000). This problem was solved by the discovery that Munc18-1 in addition of binding to the closed conformation of STX1 was also able to bind to the assembled tetrameric SNARE complex (Sudhof and Rothman, 2009). It was proposed that Munc18-1 switches its binding mode during the Munc13-regulated (see below) conformational transition of Syntaxin proteins to their “open” form that allows engagement with other SNARE partners (Sudhof and Rizo, 2011). Once the transition completed Munc18 directly participates in the fusion reaction. Phosphorylation events mediated by protein kinase C shown to phosphorylate Ser316 and Ser313 in Munc18-1 as well as cyclin dependent kinase phosphorylating Thr574 (Figure 4A) may also participate in such regulatory events (Fletcher et al., 1999; Snyder et al., 2006; Wierda et al., 2007). The fusion enhancing role of Munc18 was directly demonstrated in biochemical reconstitution experiments (Shen et al., 2007). Furthermore, structural data showed that Munc18-1 binds the assembled SNARE complex at the C-terminal end close to membranes suggesting that Munc18 might cooperate with the SNARE complex by providing a supplementary pulling force (Carr and Rizo, 2010). Nevertheless, its physiological function may even be more complex as Munc18 proteins may promote fusion also by other mechanism that may relate to their ability to interact with other fusion regulatory proteins such as Mints (Ho et al., 2006), Doc2 (Higashio et al., 2008), Granuphilin (Fukuda et al., 2005), or Cab45 (Lam et al., 2007). Besides promotion of fusion it has been reported that Munc18 proteins also regulate steps such as vesicle translocation, vesicle tethering and vesicle docking (Burgoyne et al., 2009).


The SNARE Machinery in Mast Cell Secretion.

Lorentz A, Baumann A, Vitte J, Blank U - Front Immunol (2012)

Domain structure of Munc18-1 (A) and Munc13-1 (B) as adapted from Koch et al. (2000); Misura et al. (2000); Li et al. (2011). Numbers above indicate protein or domain boundaries. For Munc18-1 domain boundaries are also directly included in the inset. The Munc18-1 protein contains three domains (with domain 3 being divided in D3a and D3b). According to crystal structure analysis the molecule adopts a horseshoe like structure that holds the STX-bound molecule in its closed conformation. Contact surfaces reside in D1 and D3a, which form the bottom ends of the horseshoe, while D2 and D3b form the upper end. Domain 3b includes the so-called Sly 1 homology domain containing the residue homologous to the Sly1-20 mutant in the yeast Sly1 protein, which bypasses the requirement for a Rab effector protein in yeast vesicular transport (Dascher et al., 1991). Above the domains are also indicated protein kinase C (Ser306 and Ser313) and Cyclin dependent kinase (Thr574) phosphorylation sites that may regulate Munc18-1 effector functions. (B) The Munc13-1 protein contains several calcium-binding C2 domains, a Diacylglycerol (DAG) C1 domain making it responsive to stimulation with PKC as well as a calmodulin binding domain. Note that the ubiquitouisly expressed isoform 13-4, which is important in mast cell exocytosis lacks the N-terminal C2a, CaMb, and C1 domains. The Mun domain shows structural similarity to thethering proteins and may play a role in the transition of the closed conformation of STX molecules by contacting either Munc18 or STX molecules (Li et al., 2011; Sudhof and Rizo, 2011).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3367400&req=5

Figure 4: Domain structure of Munc18-1 (A) and Munc13-1 (B) as adapted from Koch et al. (2000); Misura et al. (2000); Li et al. (2011). Numbers above indicate protein or domain boundaries. For Munc18-1 domain boundaries are also directly included in the inset. The Munc18-1 protein contains three domains (with domain 3 being divided in D3a and D3b). According to crystal structure analysis the molecule adopts a horseshoe like structure that holds the STX-bound molecule in its closed conformation. Contact surfaces reside in D1 and D3a, which form the bottom ends of the horseshoe, while D2 and D3b form the upper end. Domain 3b includes the so-called Sly 1 homology domain containing the residue homologous to the Sly1-20 mutant in the yeast Sly1 protein, which bypasses the requirement for a Rab effector protein in yeast vesicular transport (Dascher et al., 1991). Above the domains are also indicated protein kinase C (Ser306 and Ser313) and Cyclin dependent kinase (Thr574) phosphorylation sites that may regulate Munc18-1 effector functions. (B) The Munc13-1 protein contains several calcium-binding C2 domains, a Diacylglycerol (DAG) C1 domain making it responsive to stimulation with PKC as well as a calmodulin binding domain. Note that the ubiquitouisly expressed isoform 13-4, which is important in mast cell exocytosis lacks the N-terminal C2a, CaMb, and C1 domains. The Mun domain shows structural similarity to thethering proteins and may play a role in the transition of the closed conformation of STX molecules by contacting either Munc18 or STX molecules (Li et al., 2011; Sudhof and Rizo, 2011).
Mentions: In contrast to SNARE proteins, less information is available concerning the function of Sec1/Munc18 (SM) proteins known to play fundamental roles in various intracellular secretory trafficking steps (Sudhof and Rothman, 2009). Sec1 mutant yeast cells have been initially identified in a genetic screen in yeast aiming to identify proteins involved in the secretory pathway (Novick et al., 1980). A defect in neurotransmitter release was also apparent for the uncoordinated18 (unc18) ortholog in nematodes (Hosono et al., 1992) and the drosophila Rop protein (Harrison et al., 1994). SM proteins contain seven family members in humans that bind to STX SNAREs (Bock et al., 2001). Three family members are mammalian uncoordinated18 (Munc18) proteins that are more specifically implicated in regulated exocytosis. They include Munc18-1 (sometimes also called Munc18a; Figure 4A), which is largely expressed in neurons and two ubiquitously expressed isoforms Munc18-2 (Munc18b) and Munc18-3 (Munc18c). They show specificity of binding for certain STX family members. Thus, Munc18-1 can interact with STX1, 2, and 3, Munc18-2 with STX1, 3, and slightly with STX2 (Hata and Südhof, 1995); Munc18-3 interacts with STX2 and 4 and to a lesser extent with STX1 (Tellam et al., 1995). Recently, Munc18-2 was also shown to interact with STX11 (Cote et al., 2009). Studies in knock-out mice have clearly underlined the important role of Munc18 proteins in regulated exocytosis. Animals deficient in Munc18-1 have a complete block of neurotransmission and mice die at birth due to a breathing defect (Verhage et al., 2000). Mice deficient in Munc18-3 are early embryonic lethal and in the heterozygous stage are glucose intolerant after receiving high-fat-diet due to a secretion defect in insulin-producing pancreatic beta cells (Oh et al., 2005). On the other hand, externalization of GLUT4 at the cell surface was enhanced in munc18-3 knock-out adipocytes at low concentration of insulin (Kanda et al., 2005). The reported essential role of Munc18 proteins in the secretory pathway was initially difficult to explain as biochemical experiments as well as crystal structure analysis of the STX1/Munc18-1 complex showed that Munc18 binding to their respective STX partners blocked the interaction with other SNAREs rather arguing for a negative regulatory function (Araki et al., 1997; Misura et al., 2000). This problem was solved by the discovery that Munc18-1 in addition of binding to the closed conformation of STX1 was also able to bind to the assembled tetrameric SNARE complex (Sudhof and Rothman, 2009). It was proposed that Munc18-1 switches its binding mode during the Munc13-regulated (see below) conformational transition of Syntaxin proteins to their “open” form that allows engagement with other SNARE partners (Sudhof and Rizo, 2011). Once the transition completed Munc18 directly participates in the fusion reaction. Phosphorylation events mediated by protein kinase C shown to phosphorylate Ser316 and Ser313 in Munc18-1 as well as cyclin dependent kinase phosphorylating Thr574 (Figure 4A) may also participate in such regulatory events (Fletcher et al., 1999; Snyder et al., 2006; Wierda et al., 2007). The fusion enhancing role of Munc18 was directly demonstrated in biochemical reconstitution experiments (Shen et al., 2007). Furthermore, structural data showed that Munc18-1 binds the assembled SNARE complex at the C-terminal end close to membranes suggesting that Munc18 might cooperate with the SNARE complex by providing a supplementary pulling force (Carr and Rizo, 2010). Nevertheless, its physiological function may even be more complex as Munc18 proteins may promote fusion also by other mechanism that may relate to their ability to interact with other fusion regulatory proteins such as Mints (Ho et al., 2006), Doc2 (Higashio et al., 2008), Granuphilin (Fukuda et al., 2005), or Cab45 (Lam et al., 2007). Besides promotion of fusion it has been reported that Munc18 proteins also regulate steps such as vesicle translocation, vesicle tethering and vesicle docking (Burgoyne et al., 2009).

Bottom Line: During an allergic response, the high-affinity IgE receptor, FcεRI, becomes cross-linked by receptor-bound IgE and antigen resulting in immediate release of pre-synthesized mediators - stored in granules - as well as in de novo synthesis of various mediators like cytokines and chemokines.Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNARE) proteins were found to play a central role in regulating membrane fusion events during exocytosis.In this review we summarize our current knowledge about the SNARE machinery and its mechanism of action in mast cell secretion.

View Article: PubMed Central - PubMed

Affiliation: Department of Nutritional Medicine, University of Hohenheim Stuttgart, Germany.

ABSTRACT
Mast cells are known as inflammatory cells which exert their functions in allergic and anaphylactic reactions by secretion of numerous inflammatory mediators. During an allergic response, the high-affinity IgE receptor, FcεRI, becomes cross-linked by receptor-bound IgE and antigen resulting in immediate release of pre-synthesized mediators - stored in granules - as well as in de novo synthesis of various mediators like cytokines and chemokines. Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNARE) proteins were found to play a central role in regulating membrane fusion events during exocytosis. In addition, several accessory regulators like Munc13, Munc18, Rab GTPases, secretory carrier membrane proteins, complexins, or synaptotagmins were found to be involved in membrane fusion. In this review we summarize our current knowledge about the SNARE machinery and its mechanism of action in mast cell secretion.

No MeSH data available.


Related in: MedlinePlus