BioPAX pathway converted from "LGI-ADAM interactions" in the Reactome database. LGI-ADAM interactions Synapse formation and maturation require multiple interactions between presynaptic and postsynaptic neurons. These interactions are mediated by a diverse set of synaptogenic proteins (Kegel et al. 2013, Siddiqui & Craig 2011). Initial synapse formation needs both the binding of secreted proteins to presynaptic and postsynaptic receptors, and the direct binding between presynaptic and postsynaptic transmembrane proteins. One class of molecules that plays an important role in cellular interactions in nervous system development and function is the leucine-rich glioma inactivated (LGI) protein family. These are secreted synaptogenic proteins consisting of an LRR (leucine-rich repeat) domain and a epilepsy-associated or EPTP (epitempin) domain (Gu et al. 2002). Both protein domains are generally involved in protein-protein interactions. Genetic and biochemical evidence suggests that the mechanism of action of LGI proteins involves binding to a subset of cell surface receptors belonging to the ADAM (a disintegrin and metalloproteinase) family, i.e. ADAM11, ADAM22 and ADAM23. These interactions play crucial role in the development and function of the vertebrate nervous system mainly mediating synaptic transmission and myelination (Kegel et al. 2013, Novak 2004, Seals & Courtneidge 2003). Authored: Garapati, Phani Vijay, 2015-03-11 Reviewed: Meijer, Dies, 2015-04-20 Edited: Garapati, Phani Vijay, 2015-03-11 LEFT-TO-RIGHT LGI1 binds ADAM22 and ADAM23 Leucine-rich glioma inactivated 1 (LGI1) is a secreted protein that interacts with ADAM (A Disintegrin And Metalloprotease) transmembrane proteins, and its mutations are linked to human epilepsy. Although LGI1 mutations can cause epilepsy, its precise functions in the CNS are still poorly understood. It has been suggested to be involved in controlling synaptic transmission at excitatory synapses and cerebellar development (Xie et al. 2015, Fukata et al. 2006). LGI1 binds simulatneously to the extracellular disintegrin domain of ADAM22 and ADAM23 with its EPTP (Epitempin) domain (Fukata et al. 2010) strengthening and stabilizing excitatory synapses. LGI1 interaction with ADAM23 modulates dendritic pruning and synapse elimination during development (Owuor et al. 2009, Zhou et al. 2009). LGI1 and ADAM22 are found to be part of a tripartite complex containing PSD95. PSD95 is expressed on the inner surface of postsynaptic neurons and with its third PDZ domain binds to ADAM22 cytoplasmic C-terminal ETSI-motif and with the first two PDZ domain in turn bind to stargazin. Stargazin is a transmembrane regulatory subunit of AMPA (alpha-amino-3- hydroxy-5-methylisoxazole-4-propionic acid)-receptors that is critical for AMPA-receptor trafficking and gating (Fukata et al. 2006). It has been suggested that LGI1 binds simultaneously ADAM23 and ADAM22, pulling pre and post-synaptic membranes together, physically stabilizing synapses containing these two proteins and strengthening neurotransmission in these synapses (Fukata et al. 2010). As mentioned earlier, LGI1 mutations result in ADPEAF (autosomal dominant partial epilepsy with auditory features) (OMIM 600512) (Kalachikov et al. 2002). Authored: Garapati, Phani Vijay, 2015-03-11 Reviewed: Meijer, Dies, 2015-04-20 Edited: Garapati, Phani Vijay, 2015-03-11 LGI1 dimer Reactome DB_ID: 5682767 extracellular region GENE ONTOLOGY GO:0005576 LGI1 Leucine-rich glioma-inactivated protein 1 LGI1_HUMAN Reactome DB_ID: 5678671 UniProt:O95970 LGI1 LGI1 EPT UNQ775/PRO1569 FUNCTION Regulates voltage-gated potassium channels assembled from KCNA1, KCNA4 and KCNAB1. It slows down channel inactivation by precluding channel closure mediated by the KCNAB1 subunit. Ligand for ADAM22 that positively regulates synaptic transmission mediated by AMPA-type glutamate receptors (By similarity). Plays a role in suppressing the production of MMP1/3 through the phosphatidylinositol 3-kinase/ERK pathway. May play a role in the control of neuroblastoma cell survival.SUBUNIT Oligomer. Interacts with KCNA1 within a complex containing KCNA1, KCNA4 and KCNAB1. Part of a complex containing ADAM22, DLG4/PSD95 and CACNG2/Stargazin (PubMed:27066583). Can bind to ADAM11 and ADAM23.TISSUE SPECIFICITY Predominantly expressed in neural tissues, especially in brain. Expression is reduced in low-grade brain tumors and significantly reduced or absent in malignant gliomas. Isoform 1 is absent in the cerebellum and is detectable in the occipital cortex and hippocampus; higher amounts are observed in the parietal and frontal cortices, putamen, and, particularly, in the temporal neocortex, where it is 3.5 times more abundant than in the hippocampus (at protein level). Isoform 3 shows the highest expression in the occipital cortex and the lowest in the hippocampus (at protein level).INDUCTION Down-regulated in neuroblastoma cells.PTM Glycosylated. Homo sapiens NCBI Taxonomy 9606 UniProt O95970 35 EQUAL 557 EQUAL Reactome Database ID Release 79 5678671 Database 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=5678671 Reactome R-HSA-5678671 1 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-5678671.1 Reactome http://www.reactome.org 2 Reactome Database ID Release 79 5682767 Database 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=5682767 Reactome R-HSA-5682767 1 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-5682767.1 ADAM22:PSD-95:stargazin Reactome DB_ID: 5682831 plasma membrane GENE ONTOLOGY GO:0005886 ADAM22 Disintegrin and metalloproteinase domain-containing protein 22 ADA22_HUMAN Reactome DB_ID: 5678678 UniProt:Q9P0K1 ADAM22 ADAM22 MDC2 FUNCTION Probable ligand for integrin in the brain. This is a non catalytic metalloprotease-like protein (PubMed:19692335). Involved in regulation of cell adhesion and spreading and in inhibition of cell proliferation. Neuronal receptor for LGI1.SUBUNIT Interacts with LGI1 (PubMed:27066583). Interacts with DLG4/PSD95 (PubMed:27066583). Also binds LGI4 (By similarity). Interacts with KCNA2 and DLG2 (By similarity). Interacts (via C-terminus) with YWHAB/14-3-3 beta and YWHAZ/14-3-3 zeta but not with YWHAE/14-3-3 epsilon or YWHAH/14-3-3 eta (PubMed:12589811, PubMed:15882968).TISSUE SPECIFICITY Highly expressed in the brain and in some high-grade but not low-grade gliomas. Detected slightly or not at all in other tissues.PTM The precursor is cleaved by a furin endopeptidase. UniProt Q9P0K1 223 EQUAL 906 EQUAL Reactome Database ID Release 79 5678678 Database 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=5678678 Reactome R-HSA-5678678 1 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-5678678.1 1 Converted from EntitySet in Reactome Gamma subunit of VGCC (Stargazin) Reactome DB_ID: 416844 CACNG2 Gamma 2 subunit of VGCC stargazin Reactome DB_ID: 210375 UniProt:Q9Y698 CACNG2 CACNG2 FUNCTION Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization. Does not show subunit-specific AMPA receptor regulation and regulates all AMPAR subunits. Thought to stabilize the calcium channel in an inactivated (closed) state.SUBUNIT The L-type calcium channel is composed of five subunits: alpha-1, alpha-2/delta, beta and gamma. Interacts with the PDZ domains of DLG4/PSD-95 and DLG1/SAP97. May interact with GOPC (By similarity). Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs). Found in a complex with GRIA1, GRIA2, GRIA3, GRIA4, CNIH2, CNIH3, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8 (By similarity). Interacts with GRIA1 and GRIA2 (PubMed:20805473). Interacts with MPP2 (By similarity).TISSUE SPECIFICITY Brain.PTM Phosphorylation of Thr-321 impairs interaction with DLG1 and DLG4.SIMILARITY Belongs to the PMP-22/EMP/MP20 family. CACNG subfamily. UniProt Q9Y698 1 EQUAL 323 EQUAL Reactome Database ID Release 79 210375 Database 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=210375 Reactome R-HSA-210375 1 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-210375.1 CACNG3 Gamma 3 subunit of VGCC stargazin Reactome DB_ID: 210465 UniProt:O60359 CACNG3 CACNG3 FUNCTION Regulates the trafficking to the somatodendritic compartment and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization. Does not show subunit-specific AMPA receptor regulation and regulates all AMPAR subunits. Thought to stabilize the calcium channel in an inactivated (closed) state.SUBUNIT The L-type calcium channel is composed of five subunits: alpha-1, alpha-2/delta, beta and gamma. Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs). Found in a complex with GRIA1, GRIA2, GRIA3, GRIA4, CNIH2, CNIH3, CACNG2, CACNG4, CACNG5, CACNG7 and CACNG8. Interacts with AP4M1 and GRIA1; associates GRIA1 with the adaptor protein complex 4 (AP-4) to target GRIA1 to the somatodendritic compartment of neurons.SIMILARITY Belongs to the PMP-22/EMP/MP20 family. CACNG subfamily. UniProt O60359 1 EQUAL 315 EQUAL Reactome Database ID Release 79 210465 Database 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=210465 Reactome R-HSA-210465 1 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-210465.1 CACNG4 Gamma 4 subunit of VGCC stargazin Reactome DB_ID: 210417 UniProt:Q9UBN1 CACNG4 CACNG4 FUNCTION Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit (PubMed:21127204). Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs), including GRIA1 and GRIA4. Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization and by mediating their resensitization (PubMed:21172611).SUBUNIT Interacts with CACNA1C. Identified in a complex with the L-type calcium channel subunits CACNA1C, CACNA2D1 and either CACNB1 or CACNB2 (PubMed:21127204). Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs) (PubMed:21172611). Interacts with GRIA1 (PubMed:21172611).TISSUE SPECIFICITY Detected in heart left ventricle.SIMILARITY Belongs to the PMP-22/EMP/MP20 family. CACNG subfamily. UniProt Q9UBN1 1 EQUAL 327 EQUAL Reactome Database ID Release 79 210417 Database 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=210417 Reactome R-HSA-210417 1 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-210417.1 CACNG8 Gamma 8 subunit of VGCC stargazin Reactome DB_ID: 210486 UniProt:Q8WXS5 CACNG8 CACNG8 CACNG6 FUNCTION Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit (By similarity). Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization and by mediating their resensitization. Does not show subunit-specific AMPA receptor regulation and regulates all AMPAR subunits.SUBUNIT Interacts with CACNA1C. Identified in a complex with the L-type calcium channel subunits CACNA1C, CACNA2D1 and either CACNB1 or CACNB2. Acts as an auxiliary subunit for AMPA-selective glutamate receptors (AMPARs). Found in a complex with GRIA1, GRIA2, GRIA3, GRIA4, CNIH2, CNIH3, CACNG2, CACNG3, CACNG4, CACNG5 and CACNG7. Interacts with CNIH2.TISSUE SPECIFICITY Detected in heart left ventricle.PTM Palmitoylated. Probably palmitoylated by ZDHHC3 and ZDHHC7.SIMILARITY Belongs to the PMP-22/EMP/MP20 family. CACNG subfamily. UniProt Q8WXS5 1 EQUAL 425 EQUAL Reactome Database ID Release 79 210486 Database 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=210486 Reactome R-HSA-210486 1 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-210486.1 Reactome Database ID Release 79 416844 Database 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=416844 Reactome R-HSA-416844 1 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-416844.1 1 DLG4 PSD-95 SAP-95 Disks large homolog 4 Reactome DB_ID: 202135 UniProt:P78352 DLG4 DLG4 PSD95 FUNCTION Postsynaptic scaffolding protein that plays a critical role in synaptogenesis and synaptic plasticity by providing a platform for the postsynaptic clustering of crucial synaptic proteins. Interacts with the cytoplasmic tail of NMDA receptor subunits and shaker-type potassium channels. Required for synaptic plasticity associated with NMDA receptor signaling. Overexpression or depletion of DLG4 changes the ratio of excitatory to inhibitory synapses in hippocampal neurons. May reduce the amplitude of ASIC3 acid-evoked currents by retaining the channel intracellularly. May regulate the intracellular trafficking of ADR1B. Also regulates AMPA-type glutamate receptor (AMPAR) immobilization at postsynaptic density keeping the channels in an activated state in the presence of glutamate and preventing synaptic depression.SUBUNIT Interacts through its PDZ domains with ANO2 and NETO1 (By similarity). Interacts through its first two PDZ domains with GRIN2A, GRIN2B, GRIN2C, GRIN2D (By similarity). Interacts with ASIC3 (By similarity). Interacts with SEMA4C (By similarity). Interacts with CXADR (By similarity). Interacts with KCND2 (By similarity). Interacts with SYNGAP1 (By similarity). Interacts with LRRC4 and LRRC4B (By similarity). Interacts with ERBB4 (PubMed:10725395). Interacts with KCNA1, KCNA2, KCNA3 and KCNA4 (PubMed:7477295). Interacts through its first PDZ domain with GRIK2, KCNA4 and CRIPT (PubMed:11744724). Interacts through its second PDZ domain with the PDZ domain of NOS1 or the C-terminus of CAPON (By similarity). Interacts through its third PDZ domain with NLGN1 and CRIPT, and probably with NLGN2 and NLGN3 (PubMed:9278515). Interacts through its guanylate kinase-like domain with KIF13B (PubMed:10859302). Interacts through its guanylate kinase-like domain with DLGAP1/GKAP, DLGAP2, DLGAP3, DLGAP4, MAP1A, BEGAIN and SIPA1L1 (By similarity). Isoform 2 interacts through an L27 domain with HGS/HRS and the first L27 domain of CASK (PubMed:12151521). Interacts with ADR1B and ANKS1B (By similarity). May interact with HTR2A (By similarity). Interacts with ADAM22 (PubMed:27066583). Interacts with KLHL17 and LGI1 (By similarity). Interacts with FRMPD4 (via C-terminus) (PubMed:19118189). Interacts with LRFN1, LRFN2 and LRFN4 (PubMed:16630835). Interacts (via N-terminal tandem pair of PDZ domains) with GPER1 (via C-terminus tail motif); the interaction is direct and induces the increase of GPER1 protein levels residing at the plasma membrane surface in a estradiol-independent manner (By similarity). Interacts (via N-terminus tandem pair of PDZ domains) with NOS1 (via N-terminal domain) (By similarity). Interacts with SHANK3 (By similarity). Interacts with KCNJ4 (By similarity). Interacts with GPR85 (PubMed:25780553). Interacts with CACNG2 and MPP2 (via the SH3-Guanylate kinase-like sub-module) (By similarity). Interacts with ADGRB1 (PubMed:23782696). Found in a complex with PRR7 and GRIN1 (By similarity). Interacts (via PDZ3 domain and to lesser degree via PDZ2 domain) with PRR7 (By similarity). Component of the postsynaptic hippocampal AMPA-type glutamate receptor (AMPAR) complex, at least composed of pore forming AMPAR subunits GRIA1, GRIA2 and GRIA3 and AMPAR auxiliary proteins SHISA6 and SHISA7. Interacts (via its first two PDZ domains) with SHISA6 and SHISA7 (via PDZ-binding motif); the interaction is direct (By similarity). Interacts with RPH3A and GRIN2A; this ternary complex regulates NMDA receptor composition at postsynaptic membranes (By similarity). Interacts with ABR and BCR (PubMed:20962234). Interacts with DGKI (via PDZ-binding motif); controls the localization of DGKI to the synapse (PubMed:21119615).TISSUE SPECIFICITY Brain.DOMAIN The PDZ domain 3 mediates interaction with ADR1B.DOMAIN The L27 domain near the N-terminus of isoform 2 is required for HGS/HRS-dependent targeting to postsynaptic density.PTM Palmitoylated (PubMed:26701913). Palmitoylation is required for targeting to postsynaptic density, plasma membrane and synapses (By similarity). Palmitoylation by ZDHHC2 occurs when the synaptic activity decreases and induces DLG4 synaptic clustering (By similarity). Palmitoylation by ZDHHC15 regulates trafficking to the postsynaptic density and function in synaptogenesis (By similarity). Palmitoylation may play a role in glutamate receptor GRIA1 synapse clustering (By similarity). Depalmitoylated by ABHD17A and ABHD17B and to a lesser extent by ABHD17C, ABHD12, ABHD13, LYPLA1 and LYPLA2 (PubMed:26701913). Undergoes rapid synaptic palmitoylation/depalmitoylation cycles during neuronal development which slow down in mature neurons (By similarity).PTM Ubiquitinated by MDM2 in response to NMDA receptor activation, leading to proteasome-mediated degradation of DLG4 which is required for AMPA receptor endocytosis.SIMILARITY Belongs to the MAGUK family. UniProt P78352 1 EQUAL 724 EQUAL Reactome Database ID Release 79 202135 Database 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=202135 Reactome R-HSA-202135 3 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-202135.3 1 Reactome Database ID Release 79 5682831 Database 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=5682831 Reactome R-HSA-5682831 1 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-5682831.1 ADAM23 Disintegrin and metalloproteinase domain-containing protein 23 ADA23_HUMAN Reactome DB_ID: 5678676 UniProt:O75077 ADAM23 ADAM23 MDC3 FUNCTION May play a role in cell-cell and cell-matrix interactions. This is a non-catalytic metalloprotease-like protein.SUBUNIT Can bind to LGI1 and LGI4 (By similarity). Ligand for integrin alpha-V/beta-3.TISSUE SPECIFICITY Highly expressed in the brain and weakly expressed in the heart. In the brain, expressed prominently in the amygdala, caudate nucleus, hypothalamus, thalamus, cerebral cortex and occipital pole.DEVELOPMENTAL STAGE Highly expressed in the fetal brain.DOMAIN A conserved motif AVN[ED]CD within the disintegrin-like domain could be involved in the binding to the integrin receptor. UniProt O75077 287 EQUAL 832 EQUAL Reactome Database ID Release 79 5678676 Database 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=5678676 Reactome R-HSA-5678676 1 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-5678676.1 ADAM22:LGI1 dimer:ADAM23 Reactome DB_ID: 5682809 1 1 1 Reactome Database ID Release 79 5682809 Database 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=5682809 Reactome R-HSA-5682809 1 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-5682809.1 Reactome Database ID Release 79 5682794 Database 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=5682794 Reactome R-HSA-5682794 1 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-5682794.1 20133599 Pubmed 2010 Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy Fukata, Yuko Lovero, Kathryn L Iwanaga, Tsuyoshi Watanabe, Atsushi Yokoi, Norihiko Tabuchi, Katsuhiko Shigemoto, Ryuichi Nicoll, Roger A Fukata, Masaki Proc. Natl. Acad. Sci. U.S.A. 107:3799-804 11431694 Pubmed 2001 Functional analysis of secreted and transmembrane proteins critical to mouse development Mitchell, K J Pinson, K I Kelly, O G Brennan, J Zupicich, J Scherz, P Leighton, P A Goodrich, L V Lu, X Avery, B J Tate, P Dill, K Pangilinan, E Wakenight, P Tessier-Lavigne, M Skarnes, W C Nat. Genet. 28:241-9 11810107 Pubmed 2002 Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features Kalachikov, Sergey Evgrafov, Oleg Ross, Barbara Winawer, Melodie Barker-Cummings, Christie Martinelli Boneschi, Filippo Choi, Chang Morozov, Pavel Das, Kamna Teplitskaya, Elita Yu, Andrew Cayanis, Eftihia Penchaszadeh, Graciela Kottmann, Andreas H Pedley, Timothy A Hauser, W Allen Ottman, Ruth Gilliam, T Conrad Nat. Genet. 30:335-41 16990550 Pubmed 2006 Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission Fukata, Yuko Adesnik, Hillel Iwanaga, Tsuyoshi Bredt, DS Nicoll, Roger A Fukata, Masaki Science 313:1792-5 23713523 Pubmed 2013 LGI proteins in the nervous system Kegel, Linde Aunin, Eerik Meijer, Dies Bermingham, John R ASN Neuro 5:167-81 19701204 Pubmed 2009 Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy Zhou, Yu-Dong Lee, Sanghoon Jin, Zhe Wright, Moriah Smith, Stephen E P Anderson, Matthew P Nat. Med. 15:1208-14 11978770 Pubmed 2002 Mutations in the LGI1/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy Morante-Redolat, José M Gorostidi-Pagola, Ana Piquer-Sirerol, Salomé Sáenz, Amets Poza, Juan J Galán, Juan Gesk, Stefan Sarafidou, Theologia Mautner, Victor-F Binelli, Simona Staub, Eike Hinzmann, Bernd French, Lisa Prud'homme, Jean-F Passarelli, Daniela Scannapieco, Paolo Tassinari, Carlo A Avanzini, Giuliano Martí-Massó, José F Kluwe, Lan Deloukas, Panagiotis Moschonas, Nicholas K Michelucci, Roberto Siebert, Reiner Nobile, Carlo Pérez-Tur, Jordi López de Munain, Adolfo Hum. Mol. Genet. 11:1119-28 25591666 Pubmed 2015 Essential roles of leucine-rich glioma inactivated 1 in the development of embryonic and postnatal cerebellum Xie, Ya-Jun Zhou, Liang Jiang, Nanwei Zhang, Nan Zou, Na Zhou, Lin Wang, Yin Cowell, John K Shen, Ying Sci Rep 5:7827 9693107 Pubmed 1998 Metalloproteinase-like, disintegrin-like, cysteine-rich proteins MDC2 and MDC3: novel human cellular disintegrins highly expressed in the brain Sagane, K Ohya, Y Hasegawa, Y Tanaka, I Biochem. J. 334:93-8 19796686 Pubmed 2009 LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology Owuor, Katherine Harel, Noam Y Englot, Dario J Hisama, Fuki Blumenfeld, Hal Strittmatter, Stephen M Mol. Cell. Neurosci. 42:448-57 LEFT-TO-RIGHT LGI1 binds ADAM11 In addition to ADAM22 and ADAM23, LGI1 also binds to ADAM11 (Sagane et al. 2008). ADAM11 is essential for a proper neuronal function because ADAM11-deficient mice showed deficits in special learning, motor coordination and nociceptive response (Takahashi et al 2006a,b). Authored: Garapati, Phani Vijay, 2015-03-11 Reviewed: Meijer, Dies, 2015-04-20 Edited: Garapati, Phani Vijay, 2015-03-11 ADAM11 Disintegrin and metalloproteinase domain-containing protein 11 ADA11_HUMAN Reactome DB_ID: 5678677 UniProt:O75078 ADAM11 ADAM11 MDC FUNCTION Probable ligand for integrin in the brain. This is a non catalytic metalloprotease-like protein.SUBUNIT Can bind to LGI1 and LGI4.TISSUE SPECIFICITY Expressed predominantly in brain. Slightly detected or not at all in other tissues.DOMAIN A conserved motif [AVN[ED]CD] within the disintegrin-like domain could be involved in the binding to the integrin receptor.PTM The precursor is cleaved by a furin endopeptidase. UniProt O75078 226 EQUAL 769 EQUAL Reactome Database ID Release 79 5678677 Database 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=5678677 Reactome R-HSA-5678677 1 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-5678677.1 LGI1 dimer:ADAM11 Reactome DB_ID: 5682792 1 1 Reactome Database ID Release 79 5682792 Database 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=5682792 Reactome R-HSA-5682792 1 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-5682792.1 Reactome Database ID Release 79 5682826 Database 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=5682826 Reactome R-HSA-5682826 1 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-5682826.1 18974846 Pubmed 2008 LGI1 and LGI4 bind to ADAM22, ADAM23 and ADAM11 Sagane, Koji Ishihama, Yasushi Sugimoto, Hachiro Int. J. Biol. Sci. 4:387-96 16729981 Pubmed 2006 Altered nociceptive response in ADAM11-deficient mice Takahashi, Eiki Sagane, Koji Nagasu, Takeshi Kuromitsu, Junro Brain Res. 1097:39-42 16504143 Pubmed 2006 Deficits in spatial learning and motor coordination in ADAM11-deficient mice Takahashi, Eiki Sagane, Koji Oki, Tohru Yamazaki, Kazuto Nagasu, Takeshi Kuromitsu, Junro BMC Neurosci 7:19 LEFT-TO-RIGHT LGI4 binds ADAM22,23,11 Leucine-rich glioma inactivated 4 (LGI4) protein is another candidate ligand for ADAM22 receptor. Schwann cells secrete LGI4, which through binding to the axonal receptor ADAM22 drives axonal ensheathment and myelination in the peripheral nervous system (PNS) but not central nervous system. LGI4 secretion defect results in inability of Schwann cells to correctly myelinate peripheral nerves, resulting in peripheral nervous system hypomyelination and the murine claw-paw phenotype (Birmingham et al. 2006). LGI4 interacts with not only ADAM22 but also interacts moderately with ADAM11 and ADAM23 (Ozkaynak et al. 2010, Sagane et al. 2008, Nishino et al. 2010). Authored: Garapati, Phani Vijay, 2015-03-11 Reviewed: Meijer, Dies, 2015-04-20 Edited: Garapati, Phani Vijay, 2015-03-11 Converted from EntitySet in Reactome ADAM22,11,23 Reactome DB_ID: 5682770 Reactome Database ID Release 79 5682770 Database 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=5682770 Reactome R-HSA-5682770 1 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-5682770.1 LGI4 Leucine-rich repeat LGI family member 4 LGI4_HUMAN Reactome DB_ID: 5678675 UniProt:Q8N135 LGI4 LGI4 LGIL3 UNQ6515/PRO21485 FUNCTION Component of Schwann cell signaling pathway(s) that controls axon segregation and myelin formation (By similarity).SUBUNIT Can bind to ADAM11, ADAM22 and ADAM23.TISSUE SPECIFICITY Widely expressed, with highest expression in brain. UniProt Q8N135 20 EQUAL 537 EQUAL Reactome Database ID Release 79 5678675 Database 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=5678675 Reactome R-HSA-5678675 1 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-5678675.1 LGI4:ADAM22,11,23 Reactome DB_ID: 5682788 1 1 Reactome Database ID Release 79 5682788 Database 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=5682788 Reactome R-HSA-5682788 1 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-5682788.1 Reactome Database ID Release 79 5682709 Database 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=5682709 Reactome R-HSA-5682709 1 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-5682709.1 20220021 Pubmed 2010 Adam22 is a major neuronal receptor for Lgi4-mediated Schwann cell signaling Ozkaynak, Ekim Abello, Gina Jaegle, Martine van Berge, Laura Hamer, Diana Kegel, Linde Driegen, Siska Sagane, Koji Bermingham, John R Meijer, Dies J. Neurosci. 30:3857-64 16341215 Pubmed 2006 The claw paw mutation reveals a role for Lgi4 in peripheral nerve development Bermingham, John R Shearin, Harold Pennington, Jamie O'Moore, Jill Jaegle, Martine Driegen, Siska van Zon, Arend Darbas, Aysel Ozkaynak, Ekim Ryu, Elizabeth J Milbrandt, Jeffrey Meijer, Dies Nat. Neurosci. 9:76-84 21068328 Pubmed 2010 Lgi4 promotes the proliferation and differentiation of glial lineage cells throughout the developing peripheral nervous system Nishino, Jinsuke Saunders, Thomas L Sagane, Koji Morrison, Sean J J. Neurosci. 30:15228-40 LEFT-TO-RIGHT LGI2 binds ADAM22,23 Leucine-rich glioma inactivated 2 (LGI2) like LIG1, is neuronally secreted and acts on ADAM (a-disintegrin-and-metalloproteinase) family of neuronal membrane proteins, which function in synapse remodelling. Based on the experiments performed in canine and rat brain it proves that LGI2 interacts with ADAM22 and ADAM23 following secretion. Truncation of Lgi2 prevents its secretion and ADAM interactions causing remitting focal-onset epilepsy in dogs between ages one and four months, which is equivalent to human two to eight years. It has been suggested that LGI2 participates in protecting the brain against seizures during the pruning phase of neurodevelopment (Seppala et al. 2011). Authored: Garapati, Phani Vijay, 2015-03-11 Reviewed: Meijer, Dies, 2015-04-20 Edited: Garapati, Phani Vijay, 2015-03-11 LGI2 Leucine-rich repeat LGI family member 2 LGI2_HUMAN Reactome DB_ID: 5678672 UniProt:Q8N0V4 LGI2 LGI2 KIAA1916 LGIL2 FUNCTION Required for the development of soma-targeting inhibitory GABAergic synapses made by parvalbumin-positive basket cells.TISSUE SPECIFICITY Brain, heart and placenta. UniProt Q8N0V4 29 EQUAL 545 EQUAL Reactome Database ID Release 79 5678672 Database 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=5678672 Reactome R-HSA-5678672 1 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-5678672.1 Converted from EntitySet in Reactome ADAM22,23 Reactome DB_ID: 5682718 Reactome Database ID Release 79 5682718 Database 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=5682718 Reactome R-HSA-5682718 1 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-5682718.1 LGI2:ADAM22,23 Reactome DB_ID: 5682820 1 1 Reactome Database ID Release 79 5682820 Database 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=5682820 Reactome R-HSA-5682820 1 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-5682820.1 Reactome Database ID Release 79 5682769 Database 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=5682769 Reactome R-HSA-5682769 1 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-5682769.1 21829378 Pubmed 2011 LGI2 truncation causes a remitting focal epilepsy in dogs Seppälä, Eija H Jokinen, Tarja S Fukata, Masaki Fukata, Yuko Webster, Matthew T Karlsson, Elinor K Kilpinen, Sami K Steffen, Frank Dietschi, Elisabeth Leeb, Tosso Eklund, Ranja Zhao, Xiaochu Rilstone, Jennifer J Lindblad-Toh, Kerstin Minassian, Berge A Lohi, Hannes PLoS Genet. 7:e1002194 LEFT-TO-RIGHT LGI3 binds ADAM22,23,synatxin1 Leucine-rich glioma inactivated 3 (LGI3) is a secreted protein and a member of LGI/epitempin family expressed in the peripheral nerve and interacts with ADAM22 and ADAM23 as well as syntaxin1 in the presynaptic SNARE complex. LGI3 is suggested to be involved in multiple functions. It induces neurite outgrowth and increases phosphorylation of the signal transduction proteins AKT and FAK (focal adhesion kinase) (Park et al. 2010). It appears to promote amyloid beta and synataxin1 endocytosis (Kimura et al. 2007, Okabayashi & Kimura 2008,2010). Authored: Garapati, Phani Vijay, 2015-03-11 Reviewed: Meijer, Dies, 2015-04-20 Edited: Garapati, Phani Vijay, 2015-03-11 LGI3 Leucine-rich repeat LGI family member 3 LGI3_HUMAN Reactome DB_ID: 5678673 UniProt:Q8N145 LGI3 LGI3 LGIL4 UNQ8190/PRO23199 FUNCTION May participate in the regulation of neuronal exocytosis.SUBUNIT Interacts with STX1A.TISSUE SPECIFICITY Widely expressed, with highest levels in brain and lung. UniProt Q8N145 31 EQUAL 548 EQUAL Reactome Database ID Release 79 5678673 Database 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=5678673 Reactome R-HSA-5678673 1 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-5678673.1 Converted from EntitySet in Reactome ADAM22,23,syntaxin1 Reactome DB_ID: 5682821 Converted from EntitySet in Reactome STX1 Reactome DB_ID: 5250514 STX1A Syntaxin-1A STX1A_HUMAN Reactome DB_ID: 449128 UniProt:Q16623 STX1A STX1A STX1 FUNCTION 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. UniProt Q16623 1 EQUAL 288 EQUAL Reactome Database ID Release 79 449128 Database 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=449128 Reactome R-HSA-449128 1 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-449128.1 STX1B Syntaxin 1B Reactome DB_ID: 181479 UniProt:P61266 STX1B STX1B STX1B1 STX1B2 FUNCTION Potentially involved in docking of synaptic vesicles at presynaptic active zones. May mediate Ca(2+)-regulation of exocytosis acrosomal reaction in sperm (By similarity).SUBUNIT Interacts with OTOF. Interacts with SYT6 and SYT8; the interaction is Ca(2+)-dependent (By similarity).PTM Phosphorylated by CK2.SIMILARITY Belongs to the syntaxin family. UniProt P61266 1 EQUAL 288 EQUAL Reactome Database ID Release 79 181479 Database 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=181479 Reactome R-HSA-181479 1 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-181479.1 Reactome Database ID Release 79 5250514 Database 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=5250514 Reactome R-HSA-5250514 1 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-5250514.1 Reactome Database ID Release 79 5682821 Database 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=5682821 Reactome R-HSA-5682821 1 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-5682821.1 LGI3;ADAM22,23,synatxin1 Reactome DB_ID: 5682751 1 1 Reactome Database ID Release 79 5682751 Database 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=5682751 Reactome R-HSA-5682751 1 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-5682751.1 Reactome Database ID Release 79 5682802 Database 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=5682802 Reactome R-HSA-5682802 1 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-5682802.1 20162351 Pubmed 2010 Leucine-rich glioma inactivated 3 induces neurite outgrowth through Akt and focal adhesion kinase Park, Woo-Jae Lim, Yun Young Kwon, Nyoun Soo Baek, Kwang Jin Kim, Dong-Seok Yun, Hye-Young Neurochem. Res. 35:789-96 20461023 Pubmed 2010 LGI3 interacts with flotillin-1 to mediate APP trafficking and exosome formation Okabayashi, Sachi Kimura, Nobuyuki Neuroreport 21:606-10 17387609 Pubmed 2007 Abeta upregulates and colocalizes with LGI3 in cultured rat astrocytes Kimura, Nobuyuki Ishii, Yoshiyuki Suzaki, Shingo Negishi, Takayuki Kyuwa, Shigeru Yoshikawa, Yasuhiro Cell. Mol. Neurobiol. 27:335-50 18628660 Pubmed 2008 Leucine-rich glioma inactivated 3 is involved in amyloid beta peptide uptake by astrocytes and endocytosis itself Okabayashi, Sachi Kimura, Nobuyuki Neuroreport 19:1175-9 Reactome Database ID Release 79 5682910 Database 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=5682910 Reactome R-HSA-5682910 2 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-5682910.2 14975408 Pubmed 2004 ADAM proteins in the brain Novak, Ulrike J Clin Neurosci 11:227-35 12514095 Pubmed 2003 The ADAMs family of metalloproteases: multidomain proteins with multiple functions Seals, Darren F Courtneidge, Sara A Genes Dev. 17:7-30