NRXN1 (human, Q9ULB1) curation notes

2026-09-30 — initial review

Identity and scope

• Q9ULB1 is the canonical neurexin-1-alpha entry (1477 aa; signal peptide, six LNS/laminin G-like domains with three interspersed EGF repeats, stalk, one TM helix at 1402-1422, 55-aa cytoplasmic tail ending ...KEYYV, a class II PDZ-binding motif). The beta isoforms from the internal promoter are a separate UniProt entry, P58400.
• UniProt annotates Ca2+-binding residues in LNS2, LNS4 and LNS6 (e.g. 329, 346, 407; 765, 782, 841; 1176, 1193, 1245, 1247) and a CASK-interaction region 1444-1470.
• The Falcon deep-research file was generated with a P58400 (beta) template header by mistake; its text is largely beta-framed but gene-level. Used as retrieval support only.

Core biology (with provenance)

• Discovery as alpha-latrotoxin receptor; synaptic surface protein PMID:1621094 PMID:1621094
• Trans-synaptic adhesion with neuroligins, splice-regulated PMID:16242404
• LRRTM2 binds only SS4-lacking neurexins and forms adhesion junctions PMID:20064387; NRXN1 is the LRRTM2 receptor PMID:20064388
• Latrophilin-1/CIRL1 PMID:22262843
• Dystroglycan, Ca2+-dependent via LNS Ca2+ site PMID:11470830
• Cerebellin-GluD tripartite bridge, SS4+ selective PMID:20537373 PMID:21356198
• GABA-A receptors PMID:20471353; the same paper: overexpressed neurexins do not increase synapse density.
• Neurexin induces postsynaptic differentiation PMID:15620359
• Human NRXN1-alpha surface trafficking and rodent NRXN1-alpha clustering of PSD-95/LRRTM2 and NLGN2/gephyrin PMID:21424692
• Cytoplasmic tail binds CASK via C-terminal residues PMID:8786425
• Alpha-neurexins: release, not synapse formation PMID:12827191; channels not directly gated PMID:17035546
• Nrxn1-alpha single KO mouse: presynaptic excitatory defect; normal social behaviour and spatial learning; enhanced rotarod learning PMID:19822762
• Human disease: biallelic loss -> Pitt-Hopkins-like syndrome 2 PMID:19896112

Caution: retracted paper

• PMID:28472659 (Chen et al. 2017 Neuron, "Conditional Deletion of All Neurexins Defines Diversity of Essential Synaptic Organizer Functions for Neurexins") carries a 2025 retraction notice in PubMed. It was fetched while researching and deliberately NOT cited. The "context-dependent specifier" framing is instead supported by PMID:12827191 and PMID:20471353.

Decisions (81 GOA rows + 1 NEW)

• ACCEPT: plasma membrane (all 8), cell surface IDA, presynaptic membrane (IEA, ISS), presynaptic active zone membrane IBA, trans-synaptic protein complex IBA, neuroligin family protein binding (IBA, ISS), cell adhesion molecule binding ISS, neurotransmitter secretion ISS, NOT neuromuscular process controlling balance (the negation is accepted).
• MODIFY: 24 x protein binding -> GO:0030165 PDZ domain binding (all partners are PDZ proteins; fragmentomics/Y2H use the cytoplasmic tail/PBM); neuron cell-cell adhesion (IEA, TAS) -> GO:0099560 synaptic membrane adhesion; signal transduction IBA -> GO:0099545 trans-synaptic signaling by trans-synaptic complex.
• REMOVE: axon guidance TAS (1992 paper only notes sequence similarity to guidance proteins); neuromuscular process controlling balance ISS (mouse rotarod shows enhanced motor learning, not a balance role; contradicts the human NOT).
• MARK_AS_OVER_ANNOTATED: calcium channel regulator activity (effect is indirect coupling, PMID:17035546); ER, nuclear membrane, vesicle, neuronal cell body ISS (transit compartments; mouse donor annotations no longer present in mouse GOA); positive regulation of synapse maturation ISS (source is an nAChR-targeting study); vocal learning and vocalization behavior rows (absent speech in severe ID is not a vocalization function).
• KEEP_AS_NON_CORE: transmembrane signaling receptor activity IBA; signaling receptor activity TAS; calcium ion binding; acetylcholine receptor binding; chemical synaptic transmission; nervous system development; synapse assembly; positive regulation of synapse assembly; the postsynaptic clustering/assembly terms (gephyrin, neuroligin, PSD-95, postsynaptic membrane assembly); glutamatergic transmission / EPSP; learning, adult behavior, social behavior.
• NEW: GO:0098632 cell-cell adhesion mediator activity (ISS, PMID:20064387). Comparator check: CLSTN1, contactins, CD200 carry it; used for neurexin in modules/neurexin_transsynaptic_adhesion.yaml.

Comparison with the neurexin module

• Consistent: GO:0098632 (via NEW) as the neurexin MF and GO:0099560 (via MODIFY of the neuron cell-cell adhesion rows) as the process; presynaptic membrane location; PAINT node PTN002227321.
• Addition beyond the module: the review also treats GO:0099545 trans-synaptic signaling and alpha-neurexin release-site organization (GO:0007269) as core; the module lists GO:0099545 as a module concept but not on the neurexin annoton.

P58400 (beta entry) GOA comparison (reference only, not reviewed)

• The beta entry has overlapping ISS rows from rat Nrxn1 beta (P0DI97) for synapse assembly, clustering terms, adhesion, NLGN binding, plus IDA rows from PMID:22750515 (FGFR1 binding / neurite outgrowth) and PMID:26078884 (DISC1/Kal-7/Rac1 signalosome gene-expression and kinase-cascade terms). It also carries the behaviour IMP rows from a beta signal-peptide variant paper (PMID:17034946). If the beta entry is reviewed, the same patient-phenotype considerations apply, and the signalling-cascade IDAs from 26078884 would need separate assessment.

2026-11-05 ORGANELLES ER batch 3 (endoplasmic reticulum rows)

• Row: GO:0005783 ISS (GO_REF:0000024, from mouse Q9CS84, BHF-UCL 2015); stays MARK_AS_OVER_ANNOTATED; reason corrected.
• The old reason said mouse GOA had no experimental annotation to the term. Wrong: QuickGO (2026-11-05) shows mouse Nrxn1 IDA GO:0005783 from BHF-UCL, PMID:19036990 (same date, 20150313); rat Q63372 carries the same ISS/ISO chain.
• Donor paper (fetched, abstract only): PMID:19036990 Epitope-tagged neurexins in cultured neurons: biosynthetic transit, ER accumulation of PDZ-motif mutants. ATP1A1/ATP1A2 transit precedent -> MARK_AS_OVER_ANNOTATED; KEEP_AS_NON_CORE would need wild-type endogenous neurexin shown in an ER pool.
• No GO:0005789 (type I protein in transit).
• Not edited (outside brief scope, flag): the same incorrect "current mouse GOA carries no experimental annotation" sentence is on the ISS rows for GO:0031965 nuclear membrane, GO:0031982 vesicle and GO:0043025 neuronal cell body; whether mouse has IDA rows for those terms from PMID:19036990 too should be checked in a follow-up.

2026-11-06 Follow-up: mouse donor annotations

The ISS rows for GO:0031965 nuclear membrane, GO:0031982 vesicle and GO:0043025 neuronal cell body said mouse Nrxn1 had no experimental annotation to these terms. QuickGO (2026-11-06) shows each has an IDA from BHF-UCL on PMID:19036990, the same tagged-neurexin transit paper behind the ER row. The reasons are corrected; the MARK_AS_OVER_ANNOTATED calls stand because that paper shows transit, not residence.