LRFN1, also called SALM2, is a brain-enriched type I single-pass synaptic adhesion-like membrane glycoprotein. Its extracellular leucine-rich-repeat, immunoglobulin-like, and fibronectin type III domains bind LAR-family receptor protein tyrosine phosphatases, while its cytoplasmic C-terminal ESTV motif binds PDZ-domain postsynaptic scaffolds. LRFN1 is concentrated at excitatory postsynaptic membranes, where rodent studies show that it organizes scaffold and glutamate-receptor clusters, supports postsynaptic-density and dendritic-spine maturation, and promotes neurite outgrowth. It also forms cis homo- and heteromeric SALM complexes. Unlike SALM3 and SALM5, SALM2 did not induce presynaptic differentiation across contacting cells in the standard coculture assay. Direct human evidence establishes LRFN1 binding to PTPRF, PTPRD, and PTPRS; most cellular evidence for its neuronal roles comes from rodent systems.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0098839 postsynaptic density membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The phylogenetic annotation places LRFN1 at the postsynaptic density membrane, consistent with the experimentally localized rat ortholog and the conserved postsynaptic role of LRFN1/SALM2. Reason: Rat RGD:1304707 is Lrfn1/Salm2 rather than another SALM paralog, and its current record carries direct experimental support for postsynaptic density membrane localization. The PANTHER node is LRFN1-subfamily specific, so this is a sound orthologous transfer of a core localization. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000690342 · LRFN1 family tree node SUPPORTS TRANSFER RGD:1304707 · rat Lrfn1/Salm2 SUPPORTS TRANSFER |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location vocabulary mapping assigns the broad membrane term to this single-pass type I membrane protein. Reason: Membrane residence is intrinsic to LRFN1 topology and is independently consistent with its plasma-membrane and postsynaptic-density-membrane records. The term is broad but correct. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0162 · membrane controlled vocabulary SUPPORTS TRANSFER |
| GO:0045202 synapse | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location vocabulary mapping places LRFN1 at the synapse, consistent with its SALM2 identity and postsynaptic enrichment. Reason: Synaptic localization is a core and appropriately broad location for LRFN1; the more specific postsynaptic density membrane annotations provide compatible, not conflicting, localization. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0258 · synapse controlled vocabulary SUPPORTS TRANSFER |
| GO:0098839 postsynaptic density membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Combined electronic methods transfer postsynaptic density membrane localization from rat Lrfn1 and a matching subcellular-location mapping. Reason: P0C7J6 is the rat Lrfn1/Salm2 ortholog, not a different SALM family member, and its current record has direct experimental localization to this compartment. The transfer is therefore subfamily- and species-appropriate. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P0C7J6 · rat Lrfn1/Salm2 SUPPORTS TRANSFER ensembl:ENSRNOP00000053905 · rat Lrfn1 protein SUPPORTS TRANSFER UniProtKB-SubCell:SL-0520 · postsynaptic density membrane controlled vocabulary SUPPORTS TRANSFER |
| GO:0005515 protein binding | IPI PMID:32822567 A Human IgSF Cell-Surface Interactome Reveals a Complex Netw... | MODIFY | Summary: The full-text human cell-surface interactome study supports binding of LRFN1/SALM2 to the three LAR-family receptor phosphatases PTPRF, PTPRD, and PTPRS, but the generic protein-binding term does not describe the adhesion- molecule context. Reason: The three exact WITH/FROM accessions encode PTPRF, PTPRD, and PTPRS. Their extracellular interactions with SALM2 are experimentally supported and occur between cell-adhesion molecules; GO:0050839 captures this more informatively than GO:0005515. The assay does not establish membrane directionality or homophilic cell-cell adhesion by LRFN1. Proposed replacements: cell adhesion molecule binding Supporting Evidence: PMID:32822567 With the exception of PTPRF-SALM4, we observed binding of all LAR-PTPRs to all SALMs |
| GO:0009986 cell surface | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfers cell-surface localization from mouse Lrfn1/Salm2 to human LRFN1. Reason: Q2WF71 and ENSMUSP00000103923 represent the mouse Lrfn1 ortholog, and the donor has an experimental cell-surface annotation. Cell-surface residence also matches LRFN1's extracellular-domain, single-pass membrane topology. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q2WF71 · mouse Lrfn1/Salm2 SUPPORTS TRANSFER ensembl:ENSMUSP00000103923 · mouse Lrfn1 protein SUPPORTS TRANSFER |
| GO:0099151 regulation of postsynaptic density assembly | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfers regulation of postsynaptic density assembly from rat Lrfn1/Salm2 to the human ortholog. Reason: The donor is the rat Lrfn1 ortholog and currently carries direct experimental support for this process. The term accurately captures LRFN1's conserved induction and organization of excitatory postsynaptic components, without importing the presynaptic-induction activities reported for other SALM paralogs. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P0C7J6 · rat Lrfn1/Salm2 SUPPORTS TRANSFER ensembl:ENSRNOP00000053905 · rat Lrfn1 protein SUPPORTS TRANSFER |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8849881 | ACCEPT | Summary: The Reactome event places human SALM2/LRFN1 with glutamate receptors at excitatory synaptic plasma membrane, supporting the broader plasma membrane annotation. Reason: LRFN1 is a single-pass cell-surface protein, and the event describes its association with AMPA and NMDA receptor complexes at excitatory synapses. Plasma membrane is correct although less specific than postsynaptic density membrane. Supporting Evidence: Reactome:R-HSA-8849881 SALM2 co localizes with both pre- and post-synaptic proteins at excitatory synapses in mature neurons. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8849891 | ACCEPT | Summary: The Reactome event describes SALM2/LRFN1 association with postsynaptic PDZ scaffolds, consistent with residence in the synaptic plasma membrane. Reason: Interaction of SALM2 with PSD-95-family scaffolds and its enrichment in synaptic fractions support the broad plasma-membrane location. The term does not incorrectly assign the presynaptic differentiation activity reported in this record specifically for SALM3 and SALM5. Supporting Evidence: Reactome:R-HSA-8849891 SALM1 (Wang et al. 2006), SALM2 (Ko et al. 2006), SALM3 and SALM5 (Mah et al. 2010) proteins are enriched in synaptic fractions. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8849900 | ACCEPT | Summary: The Reactome event models cis homo- and heteromeric SALM complexes in the membrane, supporting plasma membrane localization of SALM2/LRFN1. Reason: The location is consistent with LRFN1 topology and the membrane-confined cis complexes. Cis homomerization must not be conflated with homophilic interaction across cell junctions or with homophilic cell-cell adhesion. Supporting Evidence: Reactome:R-HSA-8849900 SALM1, SALM2, and SALM3 form homo- and heteromeric complexes in a cis manner. |
| GO:0097110 scaffold protein binding | ISO PMID:16828986 Comparative analysis of structure, expression and PSD95-bind... | NEW | Summary: Mouse Lrfn1 binds the PDZ domains of the postsynaptic scaffold PSD95 through its cytoplasmic C terminus, and human LRFN1 conserves the terminal ESTV PDZ-binding motif. Reason: GO:0097110 captures the experimentally demonstrated scaffold-binding activity more informatively than generic protein binding. This is proposed conservatively by orthology from mouse Lrfn1 rather than presented as a direct experiment in human neurons. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q2WF71 · mouse Lrfn1/Salm2 SUPPORTS TRANSFER Supporting Evidence: PMID:16828986 C-termini of Lrfn1, Lrfn2 and Lrfn4 were bound by PDZ domains of postsynaptic protein PSD95 |
| GO:0010976 positive regulation of neuron projection development | ISO PMID:18585462 Synaptic adhesion-like molecules (SALMs) promote neurite out... | NEW | Summary: SALM2 expression promotes neurite outgrowth in cultured hippocampal neurons, with both its extracellular region and C-terminal PDZ-binding region contributing to the phenotype. Reason: GO:0010976 accurately captures the direction and neurite-development scope measured with mouse SALM2 constructs in Sprague-Dawley rat hippocampal neurons. The ISO source therefore remains the mouse Lrfn1 ortholog Q2WF71; this does not assert that the phenotype has been demonstrated in human neurons or in vivo. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q2WF71 · mouse Lrfn1/Salm2 SUPPORTS TRANSFER Supporting Evidence: PMID:18585462 Over-expression of each SALM resulted in enhanced neurite outgrowth, but with different phenotypes. PMID:18585462 the C-terminal PDZ binding domains of SALMs 1-3 are required for most aspects of neurite outgrowth. |
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Download this section (compressed HTML)Q: Which of PTPRF, PTPRD, and PTPRS engages endogenous LRFN1 in human excitatory neurons, and which interactions are trans-synaptic rather than cis on the same postsynaptic membrane?
Q: Which PSD-95-family and other PDZ scaffolds occupy the LRFN1 ESTV motif at endogenous abundance, and how does this motif control postsynaptic receptor organization and neurite growth?
Q: Do LRFN1-containing cis SALM homo- or heteromers regulate surface trafficking, ectodomain avidity, or postsynaptic signaling without mediating trans-cellular homophilic adhesion?
Q: Are the excitatory-synapse, spine, and neurite phenotypes reported in rodent neurons conserved in human neurons, and under which developmental or activity states are they most important?
Experiment: Generate isogenic human induced-pluripotent-stem-cell-derived excitatory neurons carrying LRFN1 knockout, an ESTV deletion, and structure-guided LRR-Ig interface substitutions. Rescue at the endogenous locus and quantify PSD nanostructure, dendritic spines, AMPA/NMDA receptor clustering, neurite morphology, miniature synaptic currents, and presynaptic differentiation in paired cocultures.
Hypothesis: Endogenous human LRFN1 promotes excitatory postsynaptic maturation through separable extracellular LAR-PTPR-binding and intracellular ESTV-PDZ-scaffold interfaces, without acquiring SALM3/5-like presynaptic-induction activity.
Type: Endogenous human-neuron structure-function analysis
Experiment: Perturb each LAR-family receptor singly and combinatorially on defined pre- versus postsynaptic cells, combine cell-compartment-specific proximity labeling and fluorescence lifetime interaction measurements with binding-interface rescue, and relate partner occupancy to postsynaptic maturation and transmission.
Hypothesis: Human LRFN1 uses a partner-selective subset of PTPRF, PTPRD, and PTPRS in trans, while other detected ectodomain contacts can occur in cis or remain unoccupied in neurons.
Type: Direction-resolved receptor-partner epistasis
Experiment: Perform endogenous LRFN1 tail interactomics and quantitative proximity labeling in human neurons, comparing wild type with ESTV-deleted LRFN1. Validate direct PDZ interactions biochemically and measure scaffold nanoscale organization, receptor diffusion, synaptic retention, and electrophysiological rescue.
Hypothesis: The LRFN1 ESTV motif recruits a defined PSD-95-family scaffold ensemble that immobilizes glutamate receptors in postsynaptic nanodomains.
Type: PDZ-scaffold interactomics and receptor-dynamics analysis
Experiment: Define SALM2 cis interfaces by cross-linking mass spectrometry and endogenous single-molecule stoichiometry, introduce interface-specific substitutions that preserve folding and surface delivery, and test effects on SALM partner assembly, LAR-PTPR binding, PSD organization, neurite outgrowth, and cell-cell adhesion.
Hypothesis: LRFN1-containing cis SALM oligomers regulate surface avidity or trafficking but are dispensable for trans-cellular homophilic adhesion.
Type: Cis-oligomer interface dissection
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Which LAR-family receptor phosphatase interactions are physiologically occupied by endogenous human LRFN1, whether they occur predominantly in trans or can also occur in cis, and how each interaction contributes to human postsynaptic maturation remain unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Purified human LRFN1 ectodomain binds PTPRF, PTPRD, and PTPRS, mouse structural work defines a SALM2-PTPδ interface, and rodent neurons support a postsynaptic maturation role. These findings do not identify partner-specific endogenous complexes or their directionality in human neurons.
Significance: Resolving partner use and membrane directionality is necessary to connect the direct human binding activity to LRFN1's physiological neuronal process without importing the trans-synaptogenic behavior of SALM3 or SALM5.
What would resolve it: Use compartment-specific endogenous tagging and partner-selective perturbation in paired human excitatory neurons, combined with interface-mutant rescue, proximity measurements, synaptic imaging, and electrophysiology.
Provenance (the field's own admissions):
Gap: The endogenous human-neuronal requirement for the LRFN1 ESTV motif, the identity and stoichiometry of its occupied PDZ-scaffold partners, and the mechanism by which those interactions organize receptor nanodomains are not established.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Lrfn1 C termini bind PSD95 PDZ domains, SALM2 aggregation clusters PSD-95 and glutamate-receptor-associated proteins, and the human sequence conserves the ESTV motif. The available functional experiments are predominantly rodent or heterologous and do not resolve endogenous human complexes.
Significance: This intracellular linkage is the likely bridge between extracellular adhesion and postsynaptic organization, but its human partner hierarchy and causal architecture remain unknown.
What would resolve it: Compare endogenous wild-type and ESTV-deleted LRFN1 in human neurons using quantitative PDZ-scaffold interactomics, single-molecule localization imaging, receptor-mobility measurements, and matched functional rescue.
Provenance (the field's own admissions):
Gap: The physiological role, if any, of LRFN1-containing cis homo- and heteromeric SALM complexes in postsynaptic assembly or neurite development is unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: SALM2 forms same-cell homo- and heteromeric complexes, but did not mediate SALM-SALM trans adhesion in the tested assay. Complex formation therefore cannot be treated as evidence for homophilic cell-cell adhesion or for a defined stable functional complex.
Significance: Determining whether cis oligomerization controls trafficking, avidity, or signaling would explain a conserved interaction without conflating it with the paralog-specific trans organization of presynaptic terminals.
What would resolve it: Map endogenous SALM stoichiometry and cis interfaces in neurons, then disrupt those interfaces without altering surface delivery and measure LAR-PTPR binding, PSD assembly, and neurite phenotypes.
Provenance (the field's own admissions):
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