NRXN1 Membrane Protein Introduction

Introduction of NRXN1

NRXN1, encoded by the NRXN1 gene, belongs to the neurexin family, and it is a single-pass type I membrane protein. The neurexin family proteins are encoded by several unlinked genes, of which three members (NRXN1-3) are supposed to generate thousands of distinct mRNA transcripts and protein isoforms. These genes utilize two alternate promoters (α and β) and numerous alternatively spliced exons to produce extensive alternative splicing. Recently, a third promoter (γ) was reported for NRXN1 in the 3' region. Single-nucleotide polymorphisms in the NRXN1 gene have connections with Pitt-Hopkins-like syndrome-2 and may be associated with susceptibility to schizophrenia.

Basic Information of NRXN1
Protein Name	Neurexin-1
Gene Name	NRXN1
Aliases	Neurexin I-alpha
Organism	Homo sapiens (Human)
UniProt ID	Q9ULB1
Transmembrane Times	1
Length (aa)	1477
Sequence	MGTALLQRGGCFLLCLSLLLLGCWAELGSGLEFPGAEGQWTRFPKWNACCESEMSFQLKTRSARGLVLYFDDEGFCDFLELILTRGGRLQLSFSIFCAEPATLLADTPVNDGAWHSVRIRRQFRNTTLFIDQVEAKWVEVKSKRRDMTVFSGLFVGGLPPELRAAALKLTLASVREREPFKGWIRDVRVNSSQVLPVDSGEVKLDDEPPNSGGGSPCEAGEEGEGGVCLNGGVCSVVDDQAVCDCSRTGFRGKDCSQEDNNVEGLAHLMMGDQGKSKGKEEYIATFKGSEYFCYDLSQNPIQSSSDEITLSFKTLQRNGLMLHTGKSADYVNLALKNGAVSLVINLGSGAFEALVEPVNGKFNDNAWHDVKVTRNLRQHSGIGHAMVTISVDGILTTTGYTQEDYTMLGSDDFFYVGGSPSTADLPGSPVSNNFMGCLKEVVYKNNDVRLELSRLAKQGDPKMKIHGVVAFKCENVATLDPITFETPESFISLPKWNAKKTGSISFDFRTTEPNGLILFSHGKPRHQKDAKHPQMIKVDFFAIEMLDGHLYLLLDMGSGTIKIKALLKKVNDGEWYHVDFQRDGRSGTISVNTLRTPYTAPGESEILDLDDELYLGGLPENKAGLVFPTEVWTALLNYGYVGCIRDLFIDGQSKDIRQMAEVQSTAGVKPSCSKETAKPCLSNPCKNNGMCRDGWNRYVCDCSGTGYLGRSCEREATVLSYDGSMFMKIQLPVVMHTEAEDVSLRFRSQRAYGILMATTSRDSADTLRLELDAGRVKLTVNLDCIRINCNSSKGPETLFAGYNLNDNEWHTVRVVRRGKSLKLTVDDQQAMTGQMAGDHTRLEFHNIETGIITERRYLSSVPSNFIGHLQSLTFNGMAYIDLCKNGDIDYCELNARFGFRNIIADPVTFKTKSSYVALATLQAYTSMHLFFQFKTTSLDGLILYNSGDGNDFIVVELVKGYLHYVFDLGNGANLIKGSSNKPLNDNQWHNVMISRDTSNLHTVKIDTKITTQITAGARNLDLKSDLYIGGVAKETYKSLPKLVHAKEGFQGCLASVDLNGRLPDLISDALFCNGQIERGCEGPSTTCQEDSCSNQGVCLQQWDGFSCDCSMTSFSGPLCNDPGTTYIFSKGGGQITYKWPPNDRPSTRADRLAIGFSTVQKEAVLVRVDSSSGLGDYLELHIHQGKIGVKFNVGTDDIAIEESNAIINDGKYHVVRFTRSGGNATLQVDSWPVIERYPAGRQLTIFNSQATIIIGGKEQGQPFQGQLSGLYYNGLKVLNMAAENDANIAIVGNVRLVGEVPSSMTTESTATAMQSEMSTSIMETTTTLATSTARRGKPPTKEPISQTTDDILVASAECPSDDEDIDPCEPSSGGLANPTRAGGREPYPGSAEVIRESSSTTGMVVGIVAAAALCILILLYAMYKYRNRDEGSYHVDESRNYISNSAQSNGAVVKEKQPSSAKSSNKNKKNKDKEYYV

Function of NRXN1 Membrane Protein

Locating at cell-surface, neurexins can form Ca²⁺-dependent neuroligin/neurexin complexes by binding neuroligins at synapses in the central nervous system, where they function as cell adhesion molecules and receptors to involve in the formation of synaptic contacts and normal neurotransmission. Additionally, NRXN1 is also involved in the intercellular interaction, regulation of signal transmission and exocytosis secretory granules. As there are six isoforms of NRXN1, the functions of NRXN1 is isoform-specific. α-type isoforms have a long N-terminus with six laminin G-like domains, which is deeply involved in synaptic signal transmission, regulation of calcium channel activity, and regulation of postsynaptic NMDA receptors activity. Both α-type and β-type isoforms are involved in the formation and maintenance of synaptic junctions through their calcium-dependent interactions with neuroligin family members, CBLN1 or CBLN2.

Fig.1 Predicted structure of NRXN1 in the repository of SWISS-MODEL. (Bienert, 2017)

Application of NRXN1 Membrane Protein in Literature

Dabell M.P., et al. Investigation of NRXN1 deletions: clinical and molecular characterization. Am J Med Genet A. 2013 Apr;161A(4): 717-31. PubMed ID: 23495017

This article makes an investigation of NRXN1 deletions and finds that the deletions of NRXN1 in normal siblings and parents means reduced penetrance or/and variable expressivity, which may be influenced by environmental, genetic, or/and stochastic factors.
Agha Z., et.al. A de novo microdeletion in NRXN1 in a Dutch patient with mild intellectual disability, microcephaly and gonadal dysgenesis. Genet Res (Camb). 2015, 97: e19. PubMed ID: 26438105

This article shows that deletions of NRXN1 can cause microcephaly, intellectual disability, and mild dysmorphic features. However, this is the first report of such deletions being associated with gonadal dysgenesis.
Schaaf C.P., et al. Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions. Eur J Hum Genet. 2012, 20(12): 1240-7. PubMed ID: 22617343

This article performs a clinical and molecular identification of 24 patients who have intragenic deletions of NRXN1s and undergo clinical microarray analysis.
Jenkins A.K., et al. Neurexin 1 (NRXN1) splice isoform expression during human neocortical development and aging. Mol Psychiatry. 2016, 21(5): 701-6. PubMed ID: 26216298

This article demonstrates that the expression of NRXN1 is very high in the dorsolateral prefrontal cortex of human during critical developmental windows related to the onset and diagnosis of many disorders of neurodevelopmental.
Liu J.R., et al. Functional analysis of autism-associated NRXN1β gene promoter. Yi Chuan. 2015, 37(8): 801-10. PubMed ID: 26266783

This article firstly shows that the human NRXN1β gene’s minimal promoter region is located between positions +156 and -88 (-88/+156); one region (+229/+419) inhibits while two regions (+156/+149 and -88/-73) enhance the promoter activity.

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Reference

Bienert S. (2017). The SWISS-MODEL Repository - new features and functionality. Nucleic Acids Res. 45: D313-D319.

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