NRXN1

Neurexin-1-alpha is a protein that in humans is encoded by the NRXN1 gene.^[5]

NRXN1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3B3Q
Identifiers
Aliases	NRXN1, Hs.22998, PTHSL2, SCZD17, neurexin 1
External IDs	OMIM: 600565; MGI: 1096391; HomoloGene: 21005; GeneCards: NRXN1; OMA:NRXN1 - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2p16.3 Start 49,918,503 bp[1] End 51,225,575 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17|17 E5 Start 90,033,631 bp[2] End 91,093,071 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in sural nerve middle temporal gyrus superior frontal gyrus parietal lobe postcentral gyrus Brodmann area 23 entorhinal cortex primary visual cortex ventricular zone lateral nuclear group of thalamus Top expressed in medial dorsal nucleus medial geniculate nucleus lateral geniculate nucleus anterior amygdaloid area cingulate gyrus primary motor cortex dentate gyrus prefrontal cortex piriform cortex dentate gyrus of hippocampal formation granule cell More reference expression data BioGPS More reference expression data
Gene ontology Molecular function metal ion binding calcium-dependent protein binding neuroligin family protein binding signaling receptor binding transmembrane signaling receptor activity cell adhesion molecule binding protein binding type 1 fibroblast growth factor receptor binding calcium ion binding acetylcholine receptor binding calcium channel regulator activity signaling receptor activity Cellular component integral component of membrane vesicle nuclear membrane membrane endocytic vesicle axonal growth cone synapse cell surface cell junction soma endoplasmic reticulum presynaptic membrane plasma membrane integral component of presynaptic membrane presynapse integral component of plasma membrane nucleolus protein-containing complex Schaffer collateral - CA1 synapse glutamatergic synapse GABA-ergic synapse integral component of presynaptic active zone membrane Biological process calcium-dependent cell-cell adhesion via plasma membrane cell adhesion molecules receptor localization to synapse heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules NMDA glutamate receptor clustering establishment of protein localization neuron cell-cell adhesion gamma-aminobutyric acid receptor clustering neuronal signal transduction gephyrin clustering involved in postsynaptic density assembly postsynaptic density protein 95 clustering learning regulation of AMPA receptor activity negative regulation of filopodium assembly presynaptic membrane assembly regulation of NMDA receptor activity vocalization behavior neuroligin clustering involved in postsynaptic membrane assembly adult behavior positive regulation of synaptic transmission, glutamatergic postsynaptic membrane assembly cell adhesion angiogenesis positive regulation of excitatory postsynaptic potential social behavior guanylate kinase-associated protein clustering synapse assembly protein-containing complex assembly involved in synapse maturation synaptic vesicle clustering protein localization to synapse signal transduction cerebellar granule cell differentiation positive regulation of synapse assembly positive regulation of presynaptic active zone assembly positive regulation of protein localization to plasma membrane positive regulation of gene expression negative regulation of gene expression positive regulation of protein kinase A signaling neuron projection development positive regulation of peptidyl-serine phosphorylation positive regulation of fibroblast growth factor receptor signaling pathway positive regulation of protein kinase B signaling positive regulation of ERK1 and ERK2 cascade cellular response to calcium ion positive regulation of protein kinase C activity vocal learning chemical synaptic transmission regulation of insulin secretion involved in cellular response to glucose stimulus axon guidance prepulse inhibition neuromuscular process controlling balance positive regulation of synapse maturation neurotransmitter secretion regulation of grooming behavior synaptic membrane adhesion regulation of synaptic vesicle cycle regulation of postsynaptic specialization assembly regulation of presynapse assembly regulation of postsynaptic density assembly trans-synaptic signaling by endocannabinoid Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 9378 18189 Ensembl ENSG00000179915 ENSMUSG00000024109 UniProt P58400 Q9ULB1 Q49A31 P0DI97 Q9CS84 RefSeq (mRNA) NM_001135659 NM_004801 NM_138735 NM_001320156 NM_001320157 NM_001330077 NM_001330078 NM_001330079 NM_001330081 NM_001330082 NM_001330083 NM_001330084 NM_001330085 NM_001330086 NM_001330087 NM_001330088 NM_001330089 NM_001330090 NM_001330091 NM_001330092 NM_001330093 NM_001330094 NM_001330095 NM_001330096 NM_001330097 NM_020252 NM_177284 NM_001346957 NM_001346958 NM_001346959 NM_001346960 NM_001346961 NM_001346962 NM_001347419 RefSeq (protein) NP_001129131 NP_001307085 NP_001307086 NP_001317006 NP_001317007 NP_001317008 NP_001317010 NP_001317011 NP_001317012 NP_001317013 NP_001317014 NP_001317015 NP_001317016 NP_001317017 NP_001317018 NP_001317019 NP_001317020 NP_001317021 NP_001317022 NP_001317023 NP_001317024 NP_001317025 NP_001317026 NP_004792 NP_620072 NP_001129131.1 NP_004792.1 NP_620072.1 NP_004792.1 NP_004792.1 NP_620072.1 NP_001333886 NP_001333887 NP_001333888 NP_001333889 NP_001333890 NP_001333891 NP_001334348 NP_064648 NP_796258 NP_001390248 NP_001390249 NP_001390250 NP_001390251 NP_001390252 NP_001390253 NP_001390254 NP_001390255 NP_001390256 NP_001390257 NP_001390258 NP_001390259 NP_001390260 NP_001390261 NP_064648.3 NP_796258.2 Location (UCSC) Chr 2: 49.92 – 51.23 Mb Chr 17: 90.03 – 91.09 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Neurexins are a family of proteins that function in the vertebrate nervous system as cell adhesion molecules and receptors. They are encoded by several unlinked genes of which two, NRXN1 and NRXN3, are among the largest known human genes. Three of the genes (NRXN1-3) utilize two alternate promoters and include numerous alternatively spliced exons to generate thousands of distinct mRNA transcripts and protein isoforms. The majority of transcripts are produced from the upstream promoter and encode alpha-neurexin isoforms; a much smaller number of transcripts are produced from the downstream promoter and encode beta-neurexin isoforms. The alpha-neurexins contain epidermal growth factor-like (EGF-like) sequences and laminin G domains, and have been shown to interact with neurexophilins. The beta-neurexins lack EGF-like sequences and contain fewer laminin G domains than alpha-neurexins.^[5]

Function

Neurexins are presynaptic membrane cell-adhesion molecules that bind primarily to neuroligins, proteins that have been associated with autism. Autism is characterized by a wide range of social and cognitive deficits, which are partially attributed to faulty synaptic communication between neurons.^[6] This lack of communication is oftentimes tied to mutations in NRXN1. Structural variants of NRXN1a (neurexin1 alpha) are consistent with mutations predisposing autism.^[7] These alpha neurexins are involved in communication through coupling mechanisms of calcium channels and vesicle exocytosis, to ensure that neurotransmitters are properly released. They are specifically required for glutamate and GABA release.^[8] Implications of neurexin involvement in autism have been determined through deletion in coding exons of NRXN1a, particularly in knockout mice models. These mice showed impaired social functioning, decreased motor response in new situations, and increased aggressive behavior in males.^[6] Social functioning was of major relevance for this gene and its association with autism spectrum disorder.

Genomics

The gene is found in a single copy on the short arm of chromosome 2 (2p16.3). The gene is 1,112,187 bases in length, is located on the Crick (minus) strand and encodes a protein of 1,477 amino acids (molecular weight 161.883 kDa).

Mutations of this gene that interrupt its expression have been associated with schizophrenia, autism, and intellectual disability (NRXN1 mutations and brain disorders).

Interactions

NRXN1 has been shown to interact with NLGN1.^[9][10]

References

1. GRCh38: Ensembl release 89: ENSG00000179915 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000024109 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: NRXN1 neurexin 1".
6. Grayton H.; Missler M.; Collier D.; Fernandes C. (2013). "Altered Social Behaviours in Neurexin 1α Knockout Mice Resemble Core Symptoms in Neurodevelopmental Disorders". PLOS ONE. 8 (6): e67114. Bibcode:2013PLoSO...867114G. doi:10.1371/journal.pone.0067114. PMC 3696036. PMID 23840597.
7. Yan J.; Noltner K.; Feng J.; Li W.; Schroer R.; Skinner C.; Zeng W.; Schwartz C.E.; Sommer S.S. (2008). "Neurexin 1alpha structural variants associated with autism". Neurosci Lett. 438 (3): 368–70. doi:10.1016/j.neulet.2008.04.074. PMID 18490107. S2CID 7520448.
8. Missler M.; Zhang W.; Rohlmann A.; Kattenstroth G.; Hammer R.E.; Gottmann K.; Sudhof T.C. (2003). "Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis". Nature. 423 (6943): 939–948. Bibcode:2003Natur.423..939M. doi:10.1038/nature01755. PMID 12827191. S2CID 10315093.
9. Comoletti, Davide; Flynn Robyn; Jennings Lori L; Chubykin Alexander; Matsumura Takehito; Hasegawa Hana; Südhof Thomas C; Taylor Palmer (Dec 2003). "Characterization of the interaction of a recombinant soluble neuroligin-1 with neurexin-1beta". J. Biol. Chem. 278 (50). United States: 50497–50505. doi:10.1074/jbc.M306803200. ISSN 0021-9258. PMID 14522992.
10. Ichtchenko, K; Nguyen T; Südhof T C (Feb 1996). "Structures, alternative splicing, and neurexin binding of multiple neuroligins". J. Biol. Chem. 271 (5). UNITED STATES: 2676–2682. doi:10.1074/jbc.271.5.2676. ISSN 0021-9258. PMID 8576240.

Further reading

• Missler M, Südhof TC (1998). "Neurexins: three genes and 1001 products". Trends Genet. 14 (1): 20–26. doi:10.1016/S0168-9525(97)01324-3. PMID 9448462.
• Nakajima D, Okazaki N, Yamakawa H, et al. (2003). "Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones". DNA Res. 9 (3): 99–106. doi:10.1093/dnares/9.3.99. PMID 12168954.
• Ushkaryov YA, Petrenko AG, Geppert M, Südhof TC (1992). "Neurexins: synaptic cell surface proteins related to the alpha-latrotoxin receptor and laminin". Science. 257 (5066): 50–56. Bibcode:1992Sci...257...50U. doi:10.1126/science.1621094. PMID 1621094.
• Ichtchenko K, Nguyen T, Südhof TC (1996). "Structures, alternative splicing, and neurexin binding of multiple neuroligins". J. Biol. Chem. 271 (5): 2676–2682. doi:10.1074/jbc.271.5.2676. PMID 8576240.
• Petrenko AG, Ullrich B, Missler M, et al. (1996). "Structure and evolution of neurexophilin". J. Neurosci. 16 (14): 4360–9. doi:10.1523/JNEUROSCI.16-14-04360.1996. PMC 6578849. PMID 8699246.
• Hata Y, Butz S, Südhof TC (1996). "CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins". J. Neurosci. 16 (8): 2488–94. doi:10.1523/JNEUROSCI.16-08-02488.1996. PMC 6578772. PMID 8786425.
• Perin MS (1996). "Mirror image motifs mediate the interaction of the COOH terminus of multiple synaptotagmins with the neurexins and calmodulin". Biochemistry. 35 (43): 13808–13816. doi:10.1021/bi960853x. PMID 8901523.
• Nguyen T, Südhof TC (1997). "Binding properties of neuroligin 1 and neurexin 1beta reveal function as heterophilic cell adhesion molecules". J. Biol. Chem. 272 (41): 26032–26039. doi:10.1074/jbc.272.41.26032. PMID 9325340.
• Nagase T, Ishikawa K, Miyajima N, et al. (1998). "Prediction of the coding sequences of unidentified human genes. IX. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro". DNA Res. 5 (1): 31–39. doi:10.1093/dnares/5.1.31. PMID 9628581.
• Missler M, Hammer RE, Südhof TC (1999). "Neurexophilin binding to alpha-neurexins. A single LNS domain functions as an independently folding ligand-binding unit". J. Biol. Chem. 273 (52): 34716–34723. doi:10.1074/jbc.273.52.34716. PMID 9856994.
• Kleiderlein JJ, Nisson PE, Jessee J, et al. (1999). "CCG repeats in cDNAs from human brain". Hum. Genet. 103 (6): 666–673. doi:10.1007/s004390050889. PMID 9921901. S2CID 23696667.
• Biederer T, Südhof TC (2001). "Mints as adaptors. Direct binding to neurexins and recruitment of munc18". J. Biol. Chem. 275 (51): 39803–39806. doi:10.1074/jbc.C000656200. PMID 11036064.
• Koroll M, Rathjen FG, Volkmer H (2001). "The neural cell recognition molecule neurofascin interacts with syntenin-1 but not with syntenin-2, both of which reveal self-associating activity". J. Biol. Chem. 276 (14): 10646–10654. doi:10.1074/jbc.M010647200. PMID 11152476.
• Fukuda M, Mikoshiba K (2001). "Characterization of KIAA1427 protein as an atypical synaptotagmin (Syt XIII)". Biochem. J. 354 (Pt 2): 249–57. doi:10.1042/0264-6021:3540249. PMC 1221650. PMID 11171101.
• Fukuda M, Mikoshiba K (2001). "Synaptotagmin-like protein 1-3: a novel family of C-terminal-type tandem C2 proteins". Biochem. Biophys. Res. Commun. 281 (5): 1226–1233. doi:10.1006/bbrc.2001.4512. PMID 11243866.
• Rowen L, Young J, Birditt B, et al. (2002). "Analysis of the human neurexin genes: alternative splicing and the generation of protein diversity". Genomics. 79 (4): 587–597. doi:10.1006/geno.2002.6734. PMID 11944992.
• Tabuchi K, Südhof TC (2002). "Structure and evolution of neurexin genes: insight into the mechanism of alternative splicing". Genomics. 79 (6): 849–859. doi:10.1006/geno.2002.6780. PMID 12036300.
• Nakayama M, Kikuno R, Ohara O (2003). "Protein-protein interactions between large proteins: two-hybrid screening using a functionally classified library composed of long cDNAs". Genome Res. 12 (11): 1773–1784. doi:10.1101/gr.406902. PMC 187542. PMID 12421765.

External links

• Overview of all the structural information available in the PDB for UniProt: P58400 (Neurexin-1-beta) at the PDBe-KB.