BioPAX pathway converted from "Dopamine synaptic vesicle docking and priming" in the Reactome database.Dopamine synaptic vesicle docking and priming

Dopamine synaptic vesicle docking and priming

Dopamine loaded synaptic vesicles are docked, inside the synapse in the presynaptic cell, close to the plasma membrane. The docking brings the vesicles in close proximity to the release site to facilitate the release of dopamine. Some of the molecules involved in the docking process are STXBP1 (Munc 18), RAB3A (Rab3), RIMS1 (Rab 3 interacting molecule, RIM), BZRAP1 (RIM-binding protein), UNC13B (Munc13) and alpha-liprins. STXBP1 is an SM (Sec1/Munc18-like) protein that probably functions by wrapping around the trans-SNARE complex to catalyze membrane fusion. It binds to the amino-terminus of STX1A (syntaxin-1A) (Dulubova et al. 1999) and though it's exact role is unclear (Sudhof & Riso 2011), it is essential for membrane fusion in vivo (Khvotchev et al. 2007). During synaptic exocytosis synaptic vesicles dock with an electron-dense structure called the presynaptic active zone. This has at least four key protein components: UNC13B, RIMS1, BZRAP1 and alpha-liprins. UNC13B is essential for synaptic priming (Augustin et al. 1999). The amino-terminal zinc-finger domain of RIMS1 interacts with the amino-terminal C2a-domain of UNC13B (Lu et al. 2006). A proline-rich domain in RIMS1 interacts with an SH3 domain in BZRAP1 (Wang et al. 2000). Alpha-liprins bind the C2B domain of RIMS1 (Schoch et al. 2002). RIMS1 binds to synaptic vesicle-bound RAB3A (Lu et al. 2006) and possibly SYT1 (synaptotagmin). RIMS1 and BZRAP1 bind to N and P/Q-type calcium channels in the plasma membrane (Kaeser et al. 2011). The priming reaction brings docked but unprimed synaptic vesicles into a releasable pool. Priming involes formation of the trimeric SNARE complex between two plasma membrane proteins SNAP25 and Syntaxin and vesicular membrane protein, VAMP2.

Authored: Mahajan, SS, 2008-10-17 21:22:46Reviewed: Restituito, S, 2008-11-27 12:38:49Edited: Gillespie, ME, 2009-11-19

Reactome DB_ID: 2029017

plasma membraneGO0005886

UniProt:P60880 SNAP25

SNAP25

SNAP25SNAPFUNCTION t-SNARE involved in the molecular regulation of neurotransmitter release. May play an important role in the synaptic function of specific neuronal systems. Associates with proteins involved in vesicle docking and membrane fusion. Regulates plasma membrane recycling through its interaction with CENPF. Modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1 in pancreatic beta cells.SUBUNIT Part of the SNARE core complex containing SNAP25, VAMP2 and STX1A; this complex binds CPLX1 (PubMed:11832227). Found in a complex containing SYT1, SV2B and syntaxin-1 (By similarity). Found in a ternary complex with STX1A and VAMP8 (By similarity). Interacts with HSC70 and with SYT9, forming a complex with DNAJC5 (By similarity). The interaction with SYT9 is inhibited in presence of calcium (By similarity). Isoform 1 and isoform 2 interact with BLOC1S6 (PubMed:19546860). Interacts with CENPF (By similarity). Interacts with EQTN (By similarity). Interacts with HGS (By similarity). Interacts with KCNB1 (via N-terminus); reduces the voltage-dependent potassium channel KCNB1 activity in pancreatic beta cells (By similarity). Interacts with OTOF (By similarity). Interacts with RIMS1 (By similarity). Interacts with SNAPIN (By similarity). Interacts with STXBP6 (By similarity). Interacts with TRIM9 (By similarity). Interacts with ZDHHC13 (via ANK repeats) (By similarity). Interacts with ZDHHC17 (via ANK repeats) (PubMed:28882895, PubMed:28757145). Associates with the BLOC-1 complex (PubMed:19546860). Interacts with PLCL1 (via C2 domain) (By similarity). Interacts with PRRT2; this interaction may impair the formation of the SNARE complex (PubMed:22832103, PubMed:25915028). Interacts with alpha-synuclein/SNCA (PubMed:20798282). Interacts with PRPH2 (By similarity). Interacts with ROM1 (By similarity). Interacts with STX3 (By similarity).TISSUE SPECIFICITY Neurons of the neocortex, hippocampus, piriform cortex, anterior thalamic nuclei, pontine nuclei, and granule cells of the cerebellum.PTM Palmitoylated (PubMed:28757145). Cys-85 appears to be the main site, and palmitoylation is required for membrane association (By similarity).PTM (Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type A (BoNT/A, botA) which hydrolyzes the 197-Gln-|-Arg-198 bond and inhibits neurotransmitter release (PubMed:15592454, PubMed:9886085).PTM (Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type C (BoNT/C) which hydrolyzes the 198-Arg-|-Ala-199 bond and inhibits neurotransmitter release (PubMed:9886085, PubMed:17718519). C.botulinum type C only rarely infects humans.PTM (Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type E (BoNT/E) which hydrolyzes the 180-Arg-|-Ile-181 bond and inhibits neurotransmitter release (PubMed:9886085).MISCELLANEOUS When cloned and expressed in E.coli, where protein palmitoylation does not occur, Cys-85, Cys-88, Cys-90 and Cys-92 in the protein sequence readily form an iron-sulfur cluster.SIMILARITY Belongs to the SNAP-25 family.

Reactomehttp://www.reactome.orgHomo sapiens

NCBI Taxonomy9606UniProtP60880

S-palmitoyl-L-cysteine at 85

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S-palmitoyl-L-cysteine [MOD:00115]

S-palmitoyl-L-cysteine at 88

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Reactome DB_ID: 449128

UniProt:Q16623 STX1A

STX1A

STX1STX1AFUNCTION Plays an essential role in hormone and neurotransmitter calcium-dependent exocytosis and endocytosis (PubMed:26635000). Part of the SNARE (Soluble NSF Attachment Receptor) complex composed of SNAP25, STX1A and VAMP2 which mediates the fusion of synaptic vesicles with the presynaptic plasma membrane. STX1A and SNAP25 are localized on the plasma membrane while VAMP2 resides in synaptic vesicles. The pairing of the three SNAREs from the N-terminal SNARE motifs to the C-terminal anchors leads to the formation of the SNARE complex, which brings membranes into close proximity and results in final fusion. Participates in the calcium-dependent regulation of acrosomal exocytosis in sperm (PubMed:23091057). Plays also an important role in the exocytosis of hormones such as insulin or glucagon-like peptide 1 (GLP-1) (By similarity).SUBUNIT Part of the SNARE core complex containing SNAP25, VAMP2 and STX1A; this complex constitutes the basic catalytic machinery of the complex neurotransmitter release apparatus (PubMed:26635000). The SNARE complex interacts with CPLX1 (By similarity). Interacts with STXBP1 (PubMed:12730201, PubMed:26635000). Interacts (via C-terminus) with KCNB1 (via C-terminus); the interaction increases in a calcium-dependent manner and induces a pore-independent enhancement of exocytosis in neuroendocrine cells, chromaffin cells, pancreatic beta cells and from the soma of dorsal root ganglia (DRG) neurons (By similarity). Interacts with SYTL4 (By similarity). Interacts with STXBP6 (By similarity). Interacts with PLCL1 (via C2 domain) (By similarity). Interacts with OTOF (By similarity). Interacts with LGI3 (By similarity). Interacts with SLC6A4 (By similarity). Interacts with SYT6 and SYT8; the interaction is Ca(2+)-dependent (By similarity). Interacts with VAMP8 (PubMed:12130530). Interacts with SNAP23 (PubMed:12130530). Interacts with VAPA and SYBU (PubMed:15459722). Interacts with PRRT2 (By similarity). Interacts with SEPT8 (By similarity). Interacts with STXBP5L (By similarity). Interacts with synaptotagmin-1/SYT1 (By similarity).TISSUE SPECIFICITY Isoform 1 is highly expressed in embryonic spinal chord and ganglia and in adult cerebellum and cerebral cortex. Isoform 2 is expressed in heart, liver, fat, skeletal muscle, kidney and brain.PTM Phosphorylated by CK2 (By similarity). Phosphorylation at Ser-188 by DAPK1 significantly decreases its interaction with STXBP1.PTM Sumoylated, sumoylation is required for regulation of synaptic vesicle endocytosis.DISEASE STX1A is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region.SIMILARITY Belongs to the syntaxin family.

UniProtQ16623

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Reactome DB_ID: 210514

cytosolGO0005829

UniProt:P61764-1 STXBP1

STXBP1

STXBP1UNC18AFUNCTION Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins (By similarity). Essential for neurotransmission and binds syntaxin, a component of the synaptic vesicle fusion machinery probably in a 1:1 ratio. Can interact with syntaxins 1, 2, and 3 but not syntaxin 4. May play a role in determining the specificity of intracellular fusion reactions.SUBUNIT Interacts with SYTL4 (By similarity). Interacts with STX1A (PubMed:12730201). Interacts with alpha-synuclein/SNCA; this interaction controls SNCA self-replicating aggregation (PubMed:27597756). Interacts with RAB3A; this interaction promotes RAB3A dissociation from the vesicle membrane (By similarity). Interacts with CABP5 (By similarity).TISSUE SPECIFICITY Brain and spinal cord. Highly enriched in axons.SIMILARITY Belongs to the STXBP/unc-18/SEC1 family.

UniProtP61764-1

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594

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Reactome DB_ID: 210374

RIMS1:UNC13B:BZRAP1:Alpha-liprin [plasma membrane]

RIMS1:UNC13B:BZRAP1:Alpha-liprin

Reactome DB_ID: 210407

UniProt:Q86UR5 RIMS1

RIMS1

RIMS1Nbla00761KIAA0340RIM1RAB3IP2FUNCTION Rab effector involved in exocytosis (By similarity). May act as scaffold protein that regulates neurotransmitter release at the active zone. Essential for maintaining normal probability of neurotransmitter release and for regulating release during short-term synaptic plasticity (By similarity). Plays a role in dendrite formation by melanocytes (PubMed:23999003).SUBUNIT Binds RAB3A, RAB3B and RAB3D that have been activated by GTP-binding. Interacts with RAB3C, RAB10, RAB26 AND RAB37. Binds UNC13A. Interacts with TSPOAP1 and RIMBP2. Interacts with PPFIA3 and PPFIA4. Interacts with ERC1 (By similarity). Binds SNAP25, SYT1 and CACNA1B. Interaction with SYT1 is enhanced by calcium ions. Interaction with SNAP25 is weaker in the presence of calcium ions.TISSUE SPECIFICITY Expressed in melanocytes (PubMed:23999003). Detected in brain and retina (PubMed:23999003).PTM Phosphorylated by BRSK1.

UniProtQ86UR5

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1692

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Reactome DB_ID: 210475

UniProt:O14795 UNC13B

UNC13B

UNC13BUNC13FUNCTION Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. Is involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-depending refilling of readily releasable vesicle pool (RRP) (By similarity). Essential for synaptic vesicle maturation in a subset of excitatory/glutamatergic but not inhibitory/GABA-mediated synapses (By similarity). In collaboration with UNC13A, facilitates neuronal dense core vesicles fusion as well as controls the location and efficiency of their synaptic release (By similarity).SUBUNIT Interacts with RIMS1.TISSUE SPECIFICITY Expressed in kidney cortical epithelial cells and brain.DOMAIN The C2 domains are not involved in calcium-dependent phospholipid binding.SIMILARITY Belongs to the unc-13 family.

UniProtO14795

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1591

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Reactome DB_ID: 5483094

UniProt:O95153 TSPOAP1

TSPOAP1

KIAA0612BZRAP1RBP1RIMBP1TSPOAP1SUBUNIT Interacts with RIMS1 and RIMS2 (By similarity). Interacts with TSPO.TISSUE SPECIFICITY Predominantly expressed in brain, pituitary gland and thymus in adults. In adult brain, highest expression found in temporal lobe and the putamen, followed by amygdala, caudate nucleus, cerebral cortex, occipital and frontal lobe. A high expression level is also observed in fetal tissues like brain, heart, kidney and thymus.DOMAIN The SH3 and proline-rich domain is required for the interaction with TSPO and the second SH3 domain mediates binding to a proline-rich motif in RIMS1 and RIMS2.SIMILARITY Belongs to the RIMBP family.CAUTION PubMed:9915832 demonstrated interaction with TSPO but later PubMed:12435798 demonstrated in the rat ortholog that is not associated with TSPO in the brain.

UniProtO95153

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1857

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Converted from EntitySet in Reactome

Reactome DB_ID: 383385

Alpha-liprins [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityPPFIA1 [cytosol]PPFIA4 [cytosol]PPFIA3 [cytosol]PPFIA2 [cytosol]

UniProtQ13136UniProtO75335UniProtO75145UniProtO75334Reactome Database ID Release 75210374Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=210374ReactomeR-HSA-210374

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-210374.1

Reactome DB_ID: 210385

UniProt:O14810 CPLX1

CPLX1

CPLX1FUNCTION Positively regulates a late step in exocytosis of various cytoplasmic vesicles, such as synaptic vesicles and other secretory vesicles (PubMed:21785414). Organizes the SNAREs into a cross-linked zigzag topology that, when interposed between the vesicle and plasma membranes, is incompatible with fusion, thereby preventing SNAREs from releasing neurotransmitters until an action potential arrives at the synapse (PubMed:21785414). Also involved in glucose-induced secretion of insulin by pancreatic beta-cells. Essential for motor behavior.SUBUNIT Binds to the SNARE core complex containing SNAP25, VAMP2 and STX1A.TISSUE SPECIFICITY Nervous system. In hippocampus and cerebellum, expressed mainly by inhibitory neurons. Overexpressed in substantia nigra from patients with Parkinson disease.SIMILARITY Belongs to the complexin/synaphin family.

UniProtO14810

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Converted from EntitySet in Reactome

Reactome DB_ID: 380576

clathrin-sculpted monoamine transport vesicle membraneGO0070083

Synapsin [clathrin-sculpted monoamine transport vesicle membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity

Reactome DB_ID: 380575

Dopamine loaded synaptic vesicle [clathrin-sculpted monoamine transport vesicle membrane]

Dopamine loaded synaptic vesicle

Reactome DB_ID: 379363

UniProt:P63027 VAMP2

VAMP2

SYB2VAMP2FUNCTION Involved in the targeting and/or fusion of transport vesicles to their target membrane (By similarity). Major SNARE protein of synaptic vesicles which mediates fusion of synaptic vesicles to release neurotransmitters. Essential for fast vesicular exocytosis and activity-dependent neurotransmitter release as well as fast endocytosis that mediates rapid reuse of synaptic vesicles (By similarity) (PubMed:30929742). Modulates the gating characteristics of the delayed rectifier voltage-dependent potassium channel KCNB1.SUBUNIT Part of the SNARE core complex containing SNAP25, VAMP2 and STX1A. This complex binds to CPLX1. Interacts with BVES and STX4 (By similarity). Interacts with VAPA and VAPB. Interacts with WDFY2, PRKCZ and PRKCI (PubMed:17313651). Forms a complex with WDFY2 and PRKCZ (PubMed:17313651). Interacts (via N-terminus) with KCNB1 (via N-terminus and C-terminus); stimulates the channel inactivation rate of KCNB1 (By similarity). Interacts with SEPT8; the interaction inhibits interaction of VAMP2 with SYP. Interacts with SYP; the interaction is inhibited by interaction with SEPT8 (By similarity). Interacts with PICALM (PubMed:22118466, PubMed:21808019). Interacts with alpha-synuclein/SNCA (PubMed:20798282). Interacts with STX3 (By similarity).TISSUE SPECIFICITY Nervous system and skeletal muscle.PTM Phosphorylated by PRKCZ in vitro and this phosphorylation is increased in the presence of WDFY2.PTM (Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type B (BoNT/B, botB) which hydrolyzes the 76-Gln-|-Phe-77 bond and probably inhibits neurotransmitter release (PubMed:7803399).PTM (Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type D (BoNT/D, botD) which probably hydrolyzes the 59-Lys-|-Leu-60 bond and inhibits neurotransmitter release (PubMed:22289120). Note that humans are not known to be infected by C.botulinum type D.PTM (Microbial infection) Targeted and hydrolyzed by C.botulinum neurotoxin type F (BoNT/F, botF) which hydrolyzes the 58-Gln-|-Lys-59 bond and probably inhibits neurotransmitter release (PubMed:19543288).PTM (Microbial infection) Targeted and hydrolyzed by C.tetani tetanus toxin (tetX) which hydrolyzes the 76-Gln-|-Phe-77 bond and probably inhibits neurotransmitter release (PubMed:7803399).SIMILARITY Belongs to the synaptobrevin family.CAUTION A structure of a fragment of this protein in complex with the catalytic domain of C.botulinum neurotoxin type B (BoNT/B, botB) was reported; because of the lack of clear and continuous electron density for the VAMP2 peptide in the complex structure, the paper was retracted (PubMed:10932255, PubMed:19578378). However this protein is a substrate for BoNT/B (PubMed:7803399, PubMed:22289120).

UniProtP63027

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Reactome DB_ID: 372508

UniProt:P21579 SYT1

SYT1

SYT1SVP65SYTFUNCTION Calcium sensor that participates in triggering neurotransmitter release at the synapse (By similarity). May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse (By similarity). It binds acidic phospholipids with a specificity that requires the presence of both an acidic head group and a diacyl backbone. A Ca(2+)-dependent interaction between synaptotagmin and putative receptors for activated protein kinase C has also been reported. It can bind to at least three additional proteins in a Ca(2+)-independent manner; these are neurexins, syntaxin and AP2. Plays a role in dendrite formation by melanocytes (PubMed:23999003).SUBUNIT Homotetramer (Probable). Interacts with SCAMP5 (PubMed:19234194). Interacts with STON2 (PubMed:11381094). Forms a complex with SV2B, syntaxin 1 and SNAP25 (By similarity). Interacts with SV2A, SV2B and SV2C (By similarity). Interacts with RIMS1 (By similarity). Interacts with PRRT2 (By similarity). Interacts with DNAJC5 in a phosphorylation-dependent manner (By similarity). Interacts (via N-terminus) with RAB3A (By similarity). Interacts with SYT12 (By similarity). Interacts with calmodulin (By similarity).TISSUE SPECIFICITY Expressed in melanocytes (PubMed:23999003).DOMAIN The first C2 domain mediates Ca(2+)-dependent phospholipid binding.DOMAIN The second C2 domain mediates interaction with SV2A and probably with STN2.PTM Glycosylated.SIMILARITY Belongs to the synaptotagmin family.

UniProtP21579

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422

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Reactome DB_ID: 372544

UniProt:Q05940 SLC18A2

SLC18A2

VMAT2SVMTSLC18A2FUNCTION Involved in the ATP-dependent vesicular transport of biogenic amine neurotransmitters. Pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles (PubMed:23363473). Requisite for vesicular amine storage prior to secretion via exocytosis.SUBUNIT Interacts with SLC6A3.SIMILARITY Belongs to the major facilitator superfamily. Vesicular transporter family.

UniProtQ05940

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Reactome DB_ID: 351601

clathrin-sculpted monoamine transport vesicle lumenGO0070082

dopamine [ChEBI:18243]

dopamine

ChEBI18243

Reactome DB_ID: 372512

UniProt:P20336 RAB3A

RAB3A

RAB3AFUNCTION Small GTP-binding protein that plays a central role in regulated exocytosis and secretion. Controls the recruitment, tethering and docking of secretory vesicles to the plasma membrane (By similarity). Upon stimulation, switches to its active GTP-bound form, cycles to vesicles and recruits effectors such as RIMS1, RIMS2, Rabphilin-3A/RPH3A, RPH3AL or SYTL4 to help the docking of vesicules onto the plasma membrane (By similarity). Upon GTP hydrolysis by GTPase-activating protein, dissociates from the vesicle membrane allowing the exocytosis to proceed (By similarity). Stimulates insulin secretion through interaction with RIMS2 or RPH3AL effectors in pancreatic beta cells (By similarity). Regulates calcium-dependent lysosome exocytosis and plasma membrane repair (PMR) via the interaction with 2 effectors, SYTL4 and myosin-9/MYH9 (PubMed:27325790). Acts as a positive regulator of acrosome content secretion in sperm cells by interacting with RIMS1 (PubMed:22248876, PubMed:30599141). Plays also a role in the regulation of dopamine release by interacting with synaptotagmin I/SYT (By similarity).SUBUNIT Interacts with RIMS1 and RIMS2 (By similarity). Interacts with Rabphilin-3A/RPH3A and Rab effector Noc2/RPH3AL (By similarity). Interacts with SYTL4 (By similarity). Interacts with RAB3IP (By similarity). Interacts with SGSM1 and SGSM3 (By similarity). Interacts with SYT1 (By similarity). Interacts with MYH9; this interaction is essential for lysosome exocytosis and plasma membrane repair (PubMed:27325790). Interacts with STXBP1; this interaction promotes RAB3A dissociation from the vesicle membrane (By similarity). Interacts with SNCA (PubMed:15207266). Interacts with GDI1, GDI2, CHM and CHML; phosphorylation at Thr-86 disrupts these interactions (PubMed:29125462).TISSUE SPECIFICITY Specifically expressed in brain.PTM Phosphorylation of Thr-86 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including CHM, CHML and RAB GDP dissociation inhibitors GDI1 and GDI2.SIMILARITY Belongs to the small GTPase superfamily. Rab family.

UniProtP20336

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Reactome Database ID Release 75380575Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380575ReactomeR-HSA-380575

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380575.1

Reactome DB_ID: 380573

Docked dopamine loaded synaptic vesicle [plasma membrane]

Docked dopamine loaded synaptic vesicle

Reactome DB_ID: 2029017

S-palmitoyl-L-cysteine at 85

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Reactome DB_ID: 380576

Reactome DB_ID: 380575

Reactome Database ID Release 75380573Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380573ReactomeR-HSA-380573

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380573.1PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 380575

GO0000149

GO molecular function

Reactome Database ID Release 75380571Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380571Reactome Database ID Release 75380574Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380574ReactomeR-HSA-380574

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380574.322026965Pubmed2011Synaptic vesicle exocytosisSüdhof, Thomas CRizo, JosepCold Spring Harb Perspect Biol 3:10440375Pubmed1999Munc13-1 is essential for fusion competence of glutamatergic synaptic vesiclesAugustin, IRosenmund, CSüdhof, Thomas CBrose, NNature 400:457-6115935055Pubmed2005Munc18-1 stabilizes syntaxin 1, but is not essential for syntaxin 1 targeting and SNARE complex formationToonen, RFde Vries, KJZalm, RSüdhof, TCVerhage, MJ Neurochem 93:1393-40010748113Pubmed2000The RIM/NIM family of neuronal C2 domain proteins. Interactions with Rab3 and a new class of Src homology 3 domain proteinsWang, YSugita, SSudhof, T CJ. Biol. Chem. 275:20033-4411797009Pubmed2002RIM1alpha forms a protein scaffold for regulating neurotransmitter release at the active zoneSchoch, SusanneCastillo, Pablo EJo, TobiasMukherjee, KonarkGeppert, MartinWang, YunSchmitz, FrankMalenka, Robert CSüdhof, Thomas CNature 415:321-616732694Pubmed2006Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switchLu, JunMachius, MDulubova, IrinaDai, HanSüdhof, Thomas CTomchick, DRRizo, JosepPLoS Biol. 4:e19210449403Pubmed1999A conformational switch in syntaxin during exocytosis: role of munc18Dulubova, ISugita, SHill, SHosaka, MFernandez, ISüdhof, T CRizo, JEMBO J. 18:4372-8221241895Pubmed2011RIM proteins tether Ca2+ channels to presynaptic active zones via a direct PDZ-domain interactionKaeser, Pascal SDeng, LunbinWang, YunDulubova, IrinaLiu, XinranRizo, JosepSüdhof, Thomas CCell 144:282-9517989281Pubmed2007Dual modes of Munc18-1/SNARE interactions are coupled by functionally critical binding to syntaxin-1 N terminusKhvotchev, MDulubova, ISun, JDai, HRizo, JSüdhof, TCJ Neurosci 27:12147-5518617632Pubmed2008Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine effluxBinda, FDipace, CBowton, ERobertson, SDLute, BJFog, JUZhang, MSen, NColbran, RJGnegy, MEGether, UJavitch, JAErreger, KGalli, AMol Pharmacol 74:1101-89701566Pubmed1998Interaction of Munc-18-2 with syntaxin 3 controls the association of apical SNAREs in epithelial cellsRiento, KGalli, TJansson, SEhnholm, CLehtonen, EOlkkonen, VMJ Cell Sci 111:2681-8

ACTIVATION

Reactome Database ID Release 755674197Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5674197ReactomeR-HSA-5674197

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5674197.1

Reactome DB_ID: 5336456

LIN7:CASK:APBA1 [plasma membrane]

LIN7:CASK:APBA1

Reactome DB_ID: 373631

UniProt:O14936 CASK

CASK

LIN2CASKFUNCTION Multidomain scaffolding protein with a role in synaptic transmembrane protein anchoring and ion channel trafficking. Contributes to neural development and regulation of gene expression via interaction with the transcription factor TBR1. Binds to cell-surface proteins, including amyloid precursor protein, neurexins and syndecans. May mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1. Component of the LIN-10-LIN-2-LIN-7 complex, which associates with the motor protein KIF17 to transport vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules (By similarity).COFACTOR Unlike other protein kinases, does not require a divalent cation such as magnesium for catalytic activity.ACTIVITY REGULATION Differs from archetypal CaMK members in that the kinase domain exhibits a constitutively active conformation and the autoinhibitory region does not engage in direct contact with the ATP-binding cleft, although it still binds Ca(2+)/CAM.SUBUNIT CASK and LIN7 form two mutually exclusive tripartite complexes with APBA1 or CASKIN1 (By similarity). Component of the brain-specific heterotrimeric complex (LIN-10-LIN-2-LIN-7 complex) composed of at least APBA1, CASK, and LIN7, which associates with the motor protein KIF17 to transport vesicles along microtubules (By similarity). Forms a heterotrimeric complex with DLG1 and LIN7B via their L27 domains (By similarity). Identified in a complex with ACTN4, IQGAP1, MAGI2, NPHS1, SPTAN1 and SPTBN1 (By similarity). Part of a complex containing CASK, TBR1 and TSPYL2 (By similarity). Interacts with WHRN (By similarity). Interacts (via the PDZ, SH3 and guanylate kinase-like domains) with NRXN1 (via C-terminus) (By similarity). Interacts with CASKIN1, APBA1, LIN7(A/B/C) and L27 domain of DLG1 and isoform 2 of DLG4 (By similarity). Interacts with FCHSD2 (By similarity). Interacts with KIRREL3 (PubMed:19012874). Interacts with TBR1 (By similarity). Interacts with TSPYL2 (By similarity).TISSUE SPECIFICITY Ubiquitous. Expression is significantly greater in brain relative to kidney, lung, and liver and in fetal brain and kidney relative to lung and liver.DOMAIN The first L27 domain binds DLG1 and the second L27 domain probably binds LIN7.DOMAIN The protein kinase domain mediates the interaction with FCHSD2.SIMILARITY In the N-terminal section; belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily.SIMILARITY Belongs to the MAGUK family.

UniProtO14936

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926

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Converted from EntitySet in Reactome

Reactome DB_ID: 5336428

LIN7A,B,C [plasma membrane]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityLIN7B [plasma membrane]LIN7C [plasma membrane]LIN7A [plasma membrane]

UniProtQ9HAP6UniProtQ9NUP9UniProtO14910

Reactome DB_ID: 5336459

UniProt:Q02410 APBA1

APBA1

MINT1X11APBA1FUNCTION Putative function in synaptic vesicle exocytosis by binding to Munc18-1, an essential component of the synaptic vesicle exocytotic machinery. May modulate processing of the amyloid-beta precursor protein (APP) and hence formation of APP-beta. Component of the LIN-10-LIN-2-LIN-7 complex, which associates with the motor protein KIF17 to transport vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules (By similarity).SUBUNIT Part of a multimeric complex containing Munc18-1 and syntaxin-1. Also part of the brain-specific heterotrimeric complex LIN-10/X11-alpha, LIN-2/CASK, and LIN7. Component of the brain-specific heterotrimeric complex (LIN-10-LIN-2-LIN-7 complex) composed of at least APBA1, CASK, and LIN7, which associates with the motor protein KIF17 to transport vesicles along microtubules (By similarity). Within the complex, interacts (via PDZ domain) with the motor protein KIF17; the interaction is direct and is required for association of KIF17 with the cargo that is to be transported (By similarity). Both isoform 1 and isoform 2 bind to the cytoplasmic domain of amyloid protein (APP). Interacts (via PDZ 1 and 2 domains) with FSPB. Isoform 2, but not isoform 1, interacts (via its truncated PID domain) with active, GTP-bound RAB6A and RAB6B.TISSUE SPECIFICITY Brain and spinal cord. Isoform 2 is expressed in testis and brain, but not detected in lung, liver or spleen.DOMAIN Composed of an N-terminal domain that binds Munc18-1 and LIN-2/CASK, a middle phosphotyrosine-binding domain (PID/PTB) that mediates binding with the cytoplasmic domain of the amyloid-beta precursor protein, and two C-terminal PDZ domains thought to attach proteins to the plasma membrane.DOMAIN The autoinhibitory helix linker occludes the APP binding site.DOMAIN The PID domain, truncated by 11 amino acids, as observed in isoform 2, but not full-length, mediates the interaction with RAB6A and RAB6B.

UniProtQ02410

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837

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Reactome Database ID Release 755336456Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5336456ReactomeR-HSA-5336456

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5336456.1