LGI-ADAM interactions (Homo sapiens)

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Bibliography

1. Park WJ, Lim YY, Kwon NS, Baek KJ, Kim DS, Yun HY.; ''Leucine-rich glioma inactivated 3 induces neurite outgrowth through Akt and focal adhesion kinase.''; PubMed Europe PMC Scholia
2. Sagane K, Ishihama Y, Sugimoto H.; ''LGI1 and LGI4 bind to ADAM22, ADAM23 and ADAM11.''; PubMed Europe PMC Scholia
3. Okabayashi S, Kimura N.; ''LGI3 interacts with flotillin-1 to mediate APP trafficking and exosome formation.''; PubMed Europe PMC Scholia
4. Kegel L, Aunin E, Meijer D, Bermingham JR.; ''LGI proteins in the nervous system.''; PubMed Europe PMC Scholia
5. Ozkaynak E, Abello G, Jaegle M, van Berge L, Hamer D, Kegel L, Driegen S, Sagane K, Bermingham JR, Meijer D.; ''Adam22 is a major neuronal receptor for Lgi4-mediated Schwann cell signaling.''; PubMed Europe PMC Scholia
6. Seppälä EH, Jokinen TS, Fukata M, Fukata Y, Webster MT, Karlsson EK, Kilpinen SK, Steffen F, Dietschi E, Leeb T, Eklund R, Zhao X, Rilstone JJ, Lindblad-Toh K, Minassian BA, Lohi H.; ''LGI2 truncation causes a remitting focal epilepsy in dogs.''; PubMed Europe PMC Scholia
7. Fukata Y, Adesnik H, Iwanaga T, Bredt DS, Nicoll RA, Fukata M.; ''Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission.''; PubMed Europe PMC Scholia
8. Okabayashi S, Kimura N.; ''Leucine-rich glioma inactivated 3 is involved in amyloid beta peptide uptake by astrocytes and endocytosis itself.''; PubMed Europe PMC Scholia
9. Kimura N, Ishii Y, Suzaki S, Negishi T, Kyuwa S, Yoshikawa Y.; ''Abeta upregulates and colocalizes with LGI3 in cultured rat astrocytes.''; PubMed Europe PMC Scholia

History

External references

DataNodes

Name	Type	Database reference	Comment
ADAM11	Protein	O75078 (Uniprot-TrEMBL)
ADAM11	Protein	O75078 (Uniprot-TrEMBL)
ADAM22	Protein	Q9P0K1 (Uniprot-TrEMBL)
ADAM22,11,23	Complex	R-HSA-5682770 (Reactome)
ADAM22,23,syntaxin1	Complex	R-HSA-5682821 (Reactome)
ADAM22,23	Complex	R-HSA-5682718 (Reactome)
ADAM22:LGI1 dimer:ADAM23	Complex	R-HSA-5682809 (Reactome)
ADAM22:PSD-95:stargazin	Complex	R-HSA-5682831 (Reactome)
ADAM23	Protein	O75077 (Uniprot-TrEMBL)
ADAM23	Protein	O75077 (Uniprot-TrEMBL)
CACNG2	Protein	Q9Y698 (Uniprot-TrEMBL)
CACNG3	Protein	O60359 (Uniprot-TrEMBL)
CACNG4	Protein	Q9UBN1 (Uniprot-TrEMBL)
CACNG8	Protein	Q8WXS5 (Uniprot-TrEMBL)
LGI1	Protein	O95970 (Uniprot-TrEMBL)
LGI1 dimer:ADAM11	Complex	R-HSA-5682792 (Reactome)
LGI1 dimer	Complex	R-HSA-5682767 (Reactome)
LGI2	Protein	Q8N0V4 (Uniprot-TrEMBL)
LGI2:ADAM22,23	Complex	R-HSA-5682820 (Reactome)
LGI2	Protein	Q8N0V4 (Uniprot-TrEMBL)
LGI3	Protein	Q8N145 (Uniprot-TrEMBL)
LGI3;ADAM22,23,synatxin1	Complex	R-HSA-5682751 (Reactome)
LGI3	Protein	Q8N145 (Uniprot-TrEMBL)
LGI4	Protein	Q8N135 (Uniprot-TrEMBL)
LGI4:ADAM22,11,23	Complex	R-HSA-5682788 (Reactome)
LGI4	Protein	Q8N135 (Uniprot-TrEMBL)
PSD-95	Protein	P78352 (Uniprot-TrEMBL)
STX1		R-HSA-5250514 (Reactome)

Annotated Interactions

Source	Target	Type	Database reference	Comment
ADAM11			R-HSA-5682826 (Reactome)
ADAM22,11,23			R-HSA-5682709 (Reactome)
ADAM22,23,syntaxin1			R-HSA-5682802 (Reactome)
ADAM22,23			R-HSA-5682769 (Reactome)
	ADAM22:LGI1 dimer:ADAM23	Arrow	R-HSA-5682794 (Reactome)
ADAM22:PSD-95:stargazin			R-HSA-5682794 (Reactome)
ADAM23			R-HSA-5682794 (Reactome)
	LGI1 dimer:ADAM11	Arrow	R-HSA-5682826 (Reactome)
LGI1 dimer			R-HSA-5682794 (Reactome)
LGI1 dimer			R-HSA-5682826 (Reactome)
	LGI2:ADAM22,23	Arrow	R-HSA-5682769 (Reactome)
LGI2			R-HSA-5682769 (Reactome)
	LGI3;ADAM22,23,synatxin1	Arrow	R-HSA-5682802 (Reactome)
LGI3			R-HSA-5682802 (Reactome)
	LGI4:ADAM22,11,23	Arrow	R-HSA-5682709 (Reactome)
LGI4			R-HSA-5682709 (Reactome)
			R-HSA-5682709 (Reactome)	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).
			R-HSA-5682769 (Reactome)	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).
			R-HSA-5682794 (Reactome)	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).
			R-HSA-5682802 (Reactome)	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).
			R-HSA-5682826 (Reactome)	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).