LRFN5 (SALM5) is a neuronal type-I single-pass cell-surface adhesion protein with extracellular leucine-rich-repeat, immunoglobulin-like, and fibronectin type III domains. At synapses, its LRR-Ig ectodomain binds LAR-family receptor protein tyrosine phosphatases; isolated ectodomain fragments form 2:2 SALM5-PTPδ assemblies, and SALM5 dimerization supports induction of excitatory and inhibitory presynaptic differentiation. LRFN5 lacks the C-terminal PDZ-binding motif present in SALM1-SALM3 and therefore is not a canonical PDZ-tail recruiter of PSD-95. Its LRR region also binds HVEM/TNFRSF14 and contributes to suppression of macrophage activation and inflammatory responses in the central nervous system.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0098839 postsynaptic density membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The phylogenetic inference places LRFN5/SALM5 at the postsynaptic density membrane using a SALM5 family node and the exact rat Lrfn5 ortholog. Reason: RGD:1309357 is rat Lrfn5/SALM5, whose annotation record carries direct SALM5-specific postsynaptic-density evidence. The LRFN5-specific PANTHER node and conserved type-I synaptic membrane architecture support this core transfer without importing PDZ-scaffold interactions from SALM1-SALM3; SALM5 lacks a cytoplasmic PDZ-binding motif. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000690490 · LRFN5/SALM5 phylogenetic node SUPPORTS TRANSFER RGD:1309357 · rat Lrfn5/SALM5 SUPPORTS TRANSFER |
| GO:0009986 cell surface | IBA GO_REF:0000033 | ACCEPT | Summary: The IBA assigns cell-surface localization from the exact mouse Lrfn5 ortholog and an LRFN5/SALM5 phylogenetic node. Reason: LRFN5 is a signal-peptide-bearing, single-pass type-I membrane protein, and MGI:MGI:2144814 is mouse Lrfn5/SALM5 with direct cell-surface evidence. This is a secure core localization transfer. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2144814 · mouse Lrfn5/SALM5 SUPPORTS TRANSFER PANTHER:PTN000690490 · LRFN5/SALM5 phylogenetic node SUPPORTS TRANSFER |
| GO:0098978 glutamatergic synapse | IBA GO_REF:0000033 | ACCEPT | Summary: The IBA places LRFN5/SALM5 at glutamatergic synapses using the exact mouse ortholog and an LRFN5-specific phylogenetic node. Reason: The mouse Lrfn5 donor has gene-specific experimental evidence for localization at excitatory synapses. The transfer is consistent with SALM5's postsynaptic adhesion role and does not imply the glutamate-receptor-binding activities reported for SALM1 or SALM2. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2144814 · mouse Lrfn5/SALM5 SUPPORTS TRANSFER PANTHER:PTN000690490 · LRFN5/SALM5 phylogenetic node SUPPORTS TRANSFER |
| GO:0098982 GABA-ergic synapse | IBA GO_REF:0000033 | ACCEPT | Summary: The IBA places LRFN5/SALM5 at GABA-ergic synapses using the exact mouse ortholog and an LRFN5-specific phylogenetic node. Reason: Mouse Lrfn5 has direct SALM5-specific evidence at inhibitory synapses, so the orthology transfer is sound. This localization is distinct from the paralog-specific postsynaptic receptor-organizing roles of SALM1 and SALM2. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2144814 · mouse Lrfn5/SALM5 SUPPORTS TRANSFER PANTHER:PTN000690490 · LRFN5/SALM5 phylogenetic node SUPPORTS TRANSFER |
| GO:0099560 synaptic membrane adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: The IBA assigns synaptic membrane adhesion from a SALM5-specific phylogenetic node and the exact rat Lrfn5 ortholog. Reason: Rat SALM5 has gene-specific experimental support for transsynaptic adhesion, and human SALM5 binds all three presynaptic LAR-family receptor phosphatases. The inference reflects a core SALM5 role rather than the SALM3/LRFN4 or SALM1/SALM2 mechanisms. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000690490 · LRFN5/SALM5 phylogenetic node SUPPORTS TRANSFER RGD:1309357 · rat Lrfn5/SALM5 SUPPORTS TRANSFER |
| GO:1905606 regulation of presynapse assembly | IBA GO_REF:0000033 | MODIFY | Summary: SALM5 induces presynaptic differentiation in contacting axons, so the phylogenetic assignment is correct but lacks the experimentally supported positive direction. Reason: The exact mouse Lrfn5 donor has direct SALM5-specific presynapse- induction evidence. GO:1905608 captures positive regulation of presynapse assembly more precisely than the unsigned parent term and avoids conflating SALM5 with SALM4/LRFN3-mediated inhibition of presynapse assembly. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:2144814 · mouse Lrfn5/SALM5 SUPPORTS TRANSFER The donor experiments show induction rather than inhibition of presynaptic differentiation. PANTHER:PTN000690490 · LRFN5/SALM5 phylogenetic node SUPPORTS TRANSFER Proposed replacements: positive regulation of presynapse assembly |
| GO:0016020 membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location vocabulary mapping assigns the broad membrane term to LRFN5. Reason: Human LRFN5 has a cleaved signal peptide and a single transmembrane helix, while more specific cell-surface and synaptic membrane locations are independently supported. The broad membrane location is correct. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0162 · 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 human cell-surface interactome study supports LRFN5/SALM5 binding to PTPRF, PTPRD, and PTPRS, but generic protein binding obscures the cell-adhesion-molecule context. Reason: The exact ordered WITH/FROM set encodes the three LAR-family receptor phosphatases. Their extracellular binding to human SALM5 is directly tested and is central to transsynaptic adhesion; GO:0050839 is more informative than GO:0005515 without asserting an unsupported catalytic or receptor activity. 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 Lrfn5/SALM5 to human LRFN5. Reason: Q8BXA0 and ENSMUSP00000113123 represent the exact mouse Lrfn5 ortholog, whose record carries direct cell-surface evidence. Conserved signal-peptide and type-I membrane topology independently support transfer. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BXA0 · mouse Lrfn5/SALM5 SUPPORTS TRANSFER ensembl:ENSMUSP00000113123 · mouse Lrfn5 protein SUPPORTS TRANSFER |
| GO:0043031 negative regulation of macrophage activation | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfers SALM5-dependent suppression of macrophage activation from the exact mouse Lrfn5 ortholog. Reason: The donor is mouse Lrfn5/SALM5, not SALM3/LRFN4, and its annotation derives from direct CNS inflammation and macrophage-activation experiments. Human SALM5-HVEM binding is independently demonstrated in the same study, supporting conservation of this distinctive LRFN5 immune-regulatory role. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BXA0 · mouse Lrfn5/SALM5 SUPPORTS TRANSFER ensembl:ENSMUSP00000113123 · mouse Lrfn5 protein SUPPORTS TRANSFER |
| GO:0098839 postsynaptic density membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfers postsynaptic-density-membrane localization from the exact rat Lrfn5/SALM5 ortholog. Reason: D4A1J9 and ENSRNOP00000007600 are rat Lrfn5, whose record has direct SALM5-specific postsynaptic-density evidence. This is a secure exact- ortholog transfer and does not depend on the PDZ-binding tails of SALM1-SALM3. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:D4A1J9 · rat Lrfn5/SALM5 SUPPORTS TRANSFER ensembl:ENSRNOP00000007600 · rat Lrfn5 protein SUPPORTS TRANSFER |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfers glutamatergic-synapse localization from mouse Lrfn5/SALM5. Reason: The source is the exact mouse ortholog with gene-specific SALM5 experimental support at excitatory synapses. The localization does not imply the glutamate-receptor-binding functions reported for other SALM paralogs. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BXA0 · mouse Lrfn5/SALM5 SUPPORTS TRANSFER ensembl:ENSMUSP00000113123 · mouse Lrfn5 protein SUPPORTS TRANSFER |
| GO:0098982 GABA-ergic synapse | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfers GABA-ergic-synapse localization from mouse Lrfn5/SALM5. Reason: Mouse Lrfn5 is the exact ortholog and has SALM5-specific evidence at inhibitory synapses. This is a gene-specific transfer rather than a generic SALM-family extrapolation. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BXA0 · mouse Lrfn5/SALM5 SUPPORTS TRANSFER ensembl:ENSMUSP00000113123 · mouse Lrfn5 protein SUPPORTS TRANSFER |
| GO:0099560 synaptic membrane adhesion | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl transfers synaptic membrane adhesion from rat Lrfn5/SALM5 to the human ortholog. Reason: The donor is the exact rat ortholog with direct gene-specific support for SALM5 transsynaptic adhesion. Human SALM5 binding to LAR-family receptor phosphatases further supports this core role. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:D4A1J9 · rat Lrfn5/SALM5 SUPPORTS TRANSFER ensembl:ENSRNOP00000007600 · rat Lrfn5 protein SUPPORTS TRANSFER |
| GO:1905606 regulation of presynapse assembly | IEA GO_REF:0000107 | MODIFY | Summary: SALM5 induces presynaptic differentiation, so the exact-ortholog transfer is correct but should record the positive regulatory direction. Reason: Q8BXA0 is mouse Lrfn5/SALM5, and its donor annotation traces to direct SALM5 induction experiments. GO:1905608 captures the positive effect while distinguishing LRFN5 from the inhibitory SALM4/LRFN3 cis mechanism. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q8BXA0 · mouse Lrfn5/SALM5 SUPPORTS TRANSFER The gene-specific donor evidence shows induction of presynaptic differentiation. ensembl:ENSMUSP00000113123 · mouse Lrfn5 protein SUPPORTS TRANSFER Proposed replacements: positive regulation of presynapse assembly |
| GO:0005515 protein binding | IPI PMID:27152329 Neuron-specific SALM5 limits inflammation in the CNS via its... | MODIFY | Summary: Human SALM5 directly binds the tumor-necrosis-factor-receptor-family member HVEM/TNFRSF14, but generic protein binding hides the partner class. Reason: Q92956 is human HVEM/TNFRSF14. The study directly screened human SALM5 and human HVEM and mapped the conserved interaction; GO:0032813 precisely captures binding to a tumor necrosis factor receptor superfamily member without assigning SALM5 an intrinsic receptor-signaling activity. Proposed replacements: tumor necrosis factor receptor superfamily binding Supporting Evidence: PMID:27152329 Using hHVEM-Ig fusion protein to screen the library, we further validated the specificity of this interaction between SALM5 and HVEM. |
| GO:0043031 negative regulation of macrophage activation | ISS GO_REF:0000024 | ACCEPT | Summary: Curator-reviewed sequence-similarity transfer assigns suppression of macrophage activation from mouse Lrfn5/SALM5 to human LRFN5. Reason: Q8BXA0 is the exact mouse Lrfn5 ortholog and has direct experimental support for SALM5-mediated macrophage suppression in CNS inflammatory models. The same study directly validates human SALM5-HVEM binding, supporting the conservation judgment while keeping the mouse in-vivo context explicit. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BXA0 · mouse Lrfn5/SALM5 SUPPORTS TRANSFER |
| GO:0050728 negative regulation of inflammatory response | IDA PMID:27152329 Neuron-specific SALM5 limits inflammation in the CNS via its... | ACCEPT | Summary: SALM5 suppresses inflammatory responses in the central nervous system through its interaction with HVEM; the live occurs_in CNS extension is retained. Reason: The paper directly tests human SALM5-HVEM binding and shows SALM5- dependent suppression of inflammation in mouse CNS models. Although the in-vivo inflammatory phenotype is mouse, this is an experimental curator annotation to human LRFN5 from a full-text study that explicitly includes the human proteins; curator deference is appropriate. Supporting Evidence: PMID:27152329 We found that SALM5 suppressed lipopolysaccharide-induced inflammatory responses in the CNS and that a SALM-specific monoclonal antibody promoted inflammation in the CNS, and thereby aggravated clinical symptoms of mouse experimental autoimmune encephalomyelitis. |
| GO:0098632 cell-cell adhesion mediator activity | ISO PMID:18227064 The SALM family of adhesion-like molecules forms heteromeric... | NEW | Summary: Rat Lrfn5/SALM5 mediates homophilic trans-cellular adhesion in heterologous-cell assays, supporting transfer of cell-cell adhesion mediator activity to human LRFN5. Reason: GO:0098632 captures the demonstrated adhesion-mediating activity more precisely than generic binding. The evidence establishes homophilic SALM5-SALM5 adhesion across apposed cells, whereas the distinct SALM5-LAR-RPTP interaction supports heterophilic synaptic organization. D4A1J9 is the exact rat Lrfn5 ortholog, so the species boundary remains explicit. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:D4A1J9 · rat Lrfn5/SALM5 SUPPORTS TRANSFER Supporting Evidence: PMID:18227064 Both SALMs 4 and 5 formed homophilic, but not heterophilic associations, whereas no trans associations were formed by the other SALMs. PMID:27225731 We found that SALM5-expressing cells coaggregated with cells expressing all three LAR-RPTPs (LAR, PTPδ, and PTPσ). |
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Download this section (compressed HTML)Q: Which mini-exon combinations of PTPRF, PTPRD, and PTPRS engage endogenous LRFN5 in human neurons, and why do membrane aggregation and purified-protein assays report opposite effects of mini-exon B?
Q: Does endogenous full-length human LRFN5 form a defined 2:2 transsynaptic assembly, and which LAR-RPTP partners dominate at excitatory versus inhibitory synapses?
Q: How much of LRFN5-dependent presynaptic differentiation requires heterophilic LAR-RPTP binding versus homophilic SALM5-SALM5 adhesion?
Q: Does human neuronal LRFN5-HVEM engagement suppress microglial or macrophage activation in the CNS, and which cell-autonomous signaling steps mediate the effect?
Experiment: Create isogenic human induced-pluripotent-stem-cell-derived neurons with LRFN5 knockout, structure-guided LAR-binding substitutions, or dimer-disrupting substitutions and repair each allele at the endogenous locus. In paired pre/postsynaptic cultures, quantify surface delivery, transsynaptic proximity, synapsin and active-zone assembly, excitatory and inhibitory synapse numbers, and miniature synaptic currents.
Hypothesis: Endogenous human LRFN5 promotes presynapse assembly through an extracellular dimerization-dependent interaction with a partner-selective subset of LAR-RPTPs.
Type: Endogenous human-neuron structure-function analysis
Experiment: Express matched human PTPRF, PTPRD, and PTPRS mini-exon variants at comparable abundance, then measure SALM5 binding by SPR, cell-surface aggregation, and direction-resolved human-neuron coculture. Couple binding measurements to presynaptic differentiation and rescue with interface-specific mutants.
Hypothesis: LAR-RPTP mini-exon B has a context-dependent effect on LRFN5 binding that differs between soluble ectodomains and membrane-confined synaptic contacts.
Type: LAR-RPTP splice-code reconciliation
Experiment: Build human neuron-microglia and neuron-macrophage cocultures with cell-type- specific CRISPR disruption of LRFN5 or TNFRSF14. Restore wild-type or binding-defective proteins and measure contact-dependent cytokine responses, NF-κB pathway activation, cell-state transitions, and neuronal synaptic integrity.
Hypothesis: Human neuronal LRFN5 suppresses innate immune activation through direct engagement of HVEM on macrophages or microglia.
Type: Human CNS neuroimmune interface dissection
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: Which LAR-RPTP splice forms bind endogenous full-length LRFN5 at synapses is unresolved, especially because cell-aggregation assays and purified-protein measurements report opposite effects of mini-exon B.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: A 2016 cell-aggregation study found that mini-exon B strongly inhibits SALM5-LAR-RPTP interactions, whereas two 2018 structural and SPR studies found that mini-exon B favors PTPδ binding. These assay systems differ in constructs, membrane context, and species and do not establish the occupied splice form in vivo.
Significance: The splice code may determine when and where the SALM5 organizer is engaged and is necessary for interpreting partner-selective synaptic phenotypes.
What would resolve it: Compare matched human PTPRF, PTPRD, and PTPRS mini-exon variants using purified kinetics, membrane-tethered binding, and endogenous pre-to-postsynaptic contacts in paired human neurons.
Provenance (the field's own admissions):
Gap: The stoichiometry, membrane directionality, and partner hierarchy of endogenous full-length human LRFN5 complexes at excitatory and inhibitory synapses are not established.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human ectodomain fragments bind all three LAR-RPTPs, isolated LRR-Ig fragments form 2:2 assemblies with PTPδ, and rodent full-length SALM5 promotes presynaptic differentiation. Fragment structures and heterologous assays do not establish an obligate stable 2:2 complex or partner occupancy in human neurons.
Significance: Resolving the native assembly is required to connect the structural recognition mechanism to physiological synaptic organization without overinterpreting fragment crystallography.
What would resolve it: Endogenously tag LRFN5 and each LAR-RPTP in paired human neurons, measure direction-resolved proximity and stoichiometry, and test interface- and dimerization-mutant rescue of synaptic structure and transmission.
Provenance (the field's own admissions):
Gap: Whether LRFN5-HVEM signaling suppresses macrophage or microglial activation in human CNS tissue, and which cell type and signaling direction are essential, remain unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human SALM5 and HVEM bind directly, but the macrophage-coculture and inflammatory disease phenotypes were established in mouse systems. The available evidence does not demonstrate the anti-inflammatory process in human neural tissue or define whether HVEM is the complete macrophage-side signaling mechanism.
Significance: This distinction determines whether the conserved human binding event has the same immunoregulatory consequence and whether it can be separated from LRFN5's synaptic role.
What would resolve it: Use human neuron-microglia or neuron-macrophage cocultures with compartment- specific LRFN5 and TNFRSF14 perturbation, recombinant-interface rescue, cytokine profiling, and single-cell signaling analysis.
Provenance (the field's own admissions):
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