LNX1 is a multidomain ubiquitin-system protein whose long p80 isoform combines an N-terminal Zn-RING-Zn E3 ligase module with four C-terminal PDZ domains that recruit selected substrates. It catalyzes both degradative ubiquitination, as shown for SRC and other context-dependent targets, and regulatory non-degradative ubiquitination, as shown for RHOC. The shorter p70 isoform replaces residues 1-127 and therefore lacks the RING catalytic module while retaining the PDZ-rich interaction region; it functions primarily as a multivalent scaffold and can promote ubiquitination indirectly by recruiting other E3 ligases. LNX1 is found broadly in the cytoplasm and at cell junctions, while reported synaptic roles and locations are supported mainly by model-organism evidence.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference places LNX1 in the cytoplasm, consistent with the curated UniProt localization and the independent HPA cytosol annotation. Reason: Cytoplasmic localization is well supported for this soluble RING/PDZ protein. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1278335 · mouse Lnx1 SUPPORTS TRANSFER PANTHER:PTN002717488 · LNX1 family tree node SUPPORTS TRANSFER UniProtKB:Q8TBB1 · human LNX1 recipient SUPPORTS TRANSFER Self-reference: the target is its own IBD seed, which is expected rather than circular -- its own IDA annotation to GO:0005829 (cytosol), a descendant of this term, is one of the descendant evidences behind the IBD. The IBA then asserts the additional claim that the function is inherited rather than lineage-specific. |
| GO:0004842 ubiquitin-protein transferase activity | IBA GO_REF:0000033 | MODIFY | Summary: LNX1 is a RING-type E3 ubiquitin ligase, so the transferred ubiquitin-protein transferase activity is correct but broader than the E3-specific term. Reason: GO:0061630 specifically captures ubiquitin protein ligase activity and is preferable to the parent transferase term GO:0004842. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1278335 · mouse Lnx1 SUPPORTS TRANSFER PANTHER:PTN002717488 · LNX1 family tree node SUPPORTS TRANSFER Proposed replacements: ubiquitin protein ligase activity |
| GO:0006511 ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: The inferred process is consistent with LNX1-mediated ubiquitination and subsequent proteasomal degradation of selected substrates, including NUMB. Reason: Substrate-directed ubiquitination followed by proteasomal degradation is a core consequence of LNX1 E3 ligase activity, and the mouse ortholog supports transfer. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1278335 · mouse Lnx1 SUPPORTS TRANSFER PANTHER:PTN002717488 · LNX1 family tree node SUPPORTS TRANSFER |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic orthology and subcellular-location mappings place human LNX1 in the cytoplasm, consistent with UniProt and HPA localization records. Reason: The broad cytoplasmic location is independently corroborated and biologically compatible with LNX1's scaffold and ubiquitin-ligase roles. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026971 · ARBA cytoplasm rule SUPPORTS TRANSFER UniProtKB:O70263 · mouse Lnx1 SUPPORTS TRANSFER ensembl:ENSMUSP00000113035 · mouse Lnx1 protein SUPPORTS TRANSFER UniProtKB-SubCell:SL-0086 · cytoplasm controlled vocabulary SUPPORTS TRANSFER |
| GO:0030054 cell junction | IEA GO_REF:0000117 | ACCEPT | Summary: Rule-based localization to cell junctions is consistent with the independent HPA IDA annotation and with the junction-associated scaffold role reported for LNX1 isoform 2. Reason: The term is broad but supported by an independent experimental localization annotation. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00028333 · ARBA cell-junction rule SUPPORTS TRANSFER |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | MODIFY | Summary: The InterPro mapping recognizes the metal-coordinating RING-type zinc finger, but the generic metal-ion-binding term is less informative than zinc ion binding. Reason: LNX1 contains a PROSITE-supported RING-type zinc finger, and GO:0008270 names the relevant ion rather than using the overly broad GO:0046872. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR018957 · RING-type zinc-finger signature SUPPORTS TRANSFER Proposed replacements: zinc ion binding |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000003 | ACCEPT | Summary: EC-based mapping assigns the E3-specific ubiquitin protein ligase activity expected for LNX1's RING domain and curated catalytic reaction. Reason: GO:0061630 accurately captures the core catalytic molecular function of LNX1. Propagation Review Root cause: NO FAILURE CORE Sources checked: EC:2.3.2.27 · RING-type E3 ubiquitin transferase activity SUPPORTS TRANSFER |
| GO:0005515 protein binding | IPI PMID:16002321 Characterization of human LNX, a novel ligand of Numb protei... | MARK AS OVER ANNOTATED | Summary: The GOA row maps the partner to Q9BT40/INPP5K (alias SKIP), whereas the cached abstract names Ski-interacting protein/SNW1 (also alias SKIP); the homonymous partner identities cannot be reconciled from the cached evidence. Reason: The paper supports an LNX interaction through PDZ domains, but the GOA WITH/FROM and abstract point to different proteins that share the alias SKIP. Regardless of which partner is intended, generic protein binding is uninformative and should not define LNX1's core activity. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | Summary: This row aggregates LNX1 interactions from a proteome-scale yeast two-hybrid map (PMID:16189514). Reason: High-throughput binary interactions can identify candidates, but a generic protein-binding term across many partners is uninformative and does not establish function. |
| GO:0005515 protein binding | IPI PMID:16713569 A protein-protein interaction network for human inherited at... | MARK AS OVER ANNOTATED | Summary: A disease-focused protein-interaction network reported a binary interaction involving LNX1 (PMID:16713569). Reason: A single high-throughput interaction does not justify generic protein binding as a core molecular function. |
| GO:0005515 protein binding | IPI PMID:17936276 c-Src is a PDZ interaction partner and substrate of the E3 u... | MODIFY | Summary: c-Src binds an LNX1 PDZ domain through its C-terminal PDZ ligand and is ubiquitinated by LNX1 (PMID:17936276). Reason: The direct interaction is meaningful substrate-recognition evidence, and the specific partner class is captured by GO:1990782 rather than generic protein binding. Proposed replacements: protein tyrosine kinase binding Supporting Evidence: PMID:17936276 We demonstrate that the interaction of c-Src with LNX1 depends on the C-terminal PDZ ligand of c-Src. |
| GO:0005515 protein binding | IPI PMID:20864041 MAGE-RING protein complexes comprise a family of E3 ubiquiti... | MARK AS OVER ANNOTATED | Summary: LNX1 interacts with MAGEB18 in the study of MAGE-RING E3 ligase complexes (PMID:20864041), consistent with the UniProt-mapped MAGEB18 interaction region. Reason: This experimentally supported regulatory interaction informs E3-ligase control, but the generic protein-binding term itself is not an informative molecular function. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | MARK AS OVER ANNOTATED | Summary: The interaction was recovered in a next-generation-sequencing-based high-throughput interactome experiment (PMID:21516116). Reason: The screen provides candidate interaction evidence but generic protein binding neither specifies the binding mode nor establishes a biological role. |
| GO:0005515 protein binding | IPI PMID:24550280 Large-scale interaction profiling of PDZ domains through pro... | MARK AS OVER ANNOTATED | Summary: Proteomic peptide-phage display identified a ligand interaction for an LNX1 PDZ domain in a large-scale PDZ specificity survey (PMID:24550280). Reason: The domain-peptide result is useful interaction evidence, but GO:0005515 is too broad to capture PDZ-mediated recognition or LNX1's catalytic function. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: This row collapses numerous LNX1 binary interactions from a proteome-scale human interactome map (PMID:25416956). Reason: The large merged partner set is high-throughput screening evidence; generic protein binding is not suitable as a core function and individual candidates need validation. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | MARK AS OVER ANNOTATED | Summary: LNX1 interactions were assayed in a systematic study of interaction perturbations caused by disease-associated variants (PMID:25910212). Reason: These binary assay results are valuable for candidate prioritization, but a generic protein-binding annotation does not express an informative LNX1 function. |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | MARK AS OVER ANNOTATED | Summary: Barcode Fusion Genetics screening detected several LNX1 binary interactions in a pooled high-throughput format (PMID:27107012). Reason: Pooled interaction screening alone does not make generic protein binding a core molecular function or establish the relevance of each partner. |
| GO:0005515 protein binding | IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m... | MARK AS OVER ANNOTATED | Summary: This row represents LNX1 binary-interaction data reused in an interactome perturbation framework for developmental-disorder variants (PMID:29892012). Reason: The high-throughput interaction collection is not sufficiently mechanistic to support generic protein binding as an informative core function. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: LNX1 interactions were measured in a large-scale analysis of how human genetic variants disrupt protein interactions (PMID:31515488). Reason: The assay supports candidate binary contacts, but GO:0005515 obscures rather than clarifies LNX1's E3-ligase and PDZ-scaffold biology. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Hundreds of LNX1 partners were merged from the HuRI reference binary interactome (PMID:32296183). Reason: The exceptionally broad high-throughput partner set requires orthogonal and contextual validation; generic protein binding is not an informative core annotation. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: A neurodegenerative-disease interactome study associated LNX1 with a set of candidate binary partners (PMID:32814053). Reason: The disease-network screen is hypothesis-generating and does not establish generic protein binding as a specific molecular function of LNX1. |
| GO:0005515 protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | MARK AS OVER ANNOTATED | Summary: Quantitative fragmentomics mapped a very large set of LNX1 fragment-level interaction affinities (PMID:36115835). Reason: Fragment-level affinity mapping is useful for interaction discovery, but the merged generic protein-binding annotation is over-broad and not a core function. |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: A proteome-scale binary-interaction map detected LNX1 self-association (PMID:25416956). Reason: Homomeric interaction is more informative than generic protein binding, but a high-throughput self-interaction does not by itself define the core E3-ligase function. |
| GO:0042802 identical protein binding | IPI PMID:36115835 Quantitative fragmentomics allow affinity mapping of interac... | KEEP AS NON CORE | Summary: Quantitative fragmentomics independently detected LNX1 self-association (PMID:36115835). Reason: This corroborates homomeric binding, while its functional importance for substrate selection or ubiquitin transfer remains unresolved. |
| GO:0004842 ubiquitin-protein transferase activity | IEA GO_REF:0000107 | MODIFY | Summary: Mouse-ortholog transfer correctly identifies ubiquitin-protein transferase activity, but LNX1 is specifically a RING-type E3 ubiquitin ligase. Reason: Replace the broad parent activity with GO:0061630, which precisely represents the transferred E3 ubiquitin protein ligase function. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O70263 · mouse Lnx1 SUPPORTS TRANSFER ensembl:ENSMUSP00000113035 · mouse Lnx1 protein SUPPORTS TRANSFER Proposed replacements: ubiquitin protein ligase activity |
| GO:0030165 PDZ domain binding | IEA GO_REF:0000107 | MODIFY | Summary: Orthology transfer captures a PDZ-dependent mouse Lnx1 scaffold role but assigns the reciprocal PDZ-domain-binding activity to the protein that supplies the PDZ domains. Reason: LNX1 uses its own PDZ domains to organize interaction partners; GO:0140378 protein complex scaffold activity represents that directional activity better than binding to a PDZ domain. The transfer remains isoform-bounded because the reviewed human record assigns the endocytic scaffold role to isoform 2 by similarity. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:O70263 · mouse Lnx1 SOURCE BAD ensembl:ENSMUSP00000113035 · mouse Lnx1 protein SOURCE BAD Proposed replacements: protein complex scaffold activity |
| GO:0042802 identical protein binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Rule and orthology mappings transfer Lnx1 self-association to human LNX1, consistent with two independent human IPI rows. Reason: The transfer is corroborated by direct human interaction screens, although self-association is not yet established as central to LNX1 catalytic activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00027930 · ARBA identical-protein-binding rule SUPPORTS TRANSFER UniProtKB:O70263 · mouse Lnx1 SUPPORTS TRANSFER ensembl:ENSMUSP00000113035 · mouse Lnx1 protein SUPPORTS TRANSFER |
| GO:0060074 synapse maturation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl transfers a mouse Lnx1 annotation implicating the protein in synapse maturation. Reason: The conserved neuronal role is plausible, but it is a downstream organismal/cellular consequence rather than LNX1's core biochemical E3-ligase function in human cells. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O70263 · mouse Lnx1 SUPPORTS TRANSFER ensembl:ENSMUSP00000113035 · mouse Lnx1 protein SUPPORTS TRANSFER |
| GO:0098686 hippocampal mossy fiber to CA3 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Orthology transfer places LNX1 at the hippocampal mossy-fiber-to-CA3 synapse. Reason: This specific neuronal localization derives from mouse evidence and is best retained as a tissue-context annotation rather than a universal core location. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O70263 · mouse Lnx1 SUPPORTS TRANSFER ensembl:ENSMUSP00000113035 · mouse Lnx1 protein SUPPORTS TRANSFER |
| GO:0098794 postsynapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology transfer assigns LNX1 to the postsynapse based on mouse Lnx1. Reason: The localization is plausible for a neuronal PDZ scaffold but remains a context-specific inferred location rather than the gene product's defining function. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O70263 · mouse Lnx1 SUPPORTS TRANSFER ensembl:ENSMUSP00000113035 · mouse Lnx1 protein SUPPORTS TRANSFER |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000041 | ACCEPT | Summary: UniPathway mapping assigns protein ubiquitination, the direct biological process executed by LNX1's RING-type E3 ubiquitin ligase activity. Reason: This process accurately captures the core covalent modification mediated by LNX1. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniPathway:UPA00143 · protein ubiquitination pathway SUPPORTS TRANSFER |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localizes LNX1 to the cytosol. Reason: This direct human localization supports the broader cytoplasmic annotations and is compatible with LNX1's soluble ubiquitin-ligase and scaffold functions. |
| GO:0030054 cell junction | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localizes LNX1 to cell junctions. Reason: Direct human localization supports a junction-associated scaffold role and independently corroborates the electronic cell-junction annotation. |
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Download this section (compressed HTML)Q: Which endogenous human substrates are preferentially engaged by LNX1p80, and what determines degradative versus regulatory ubiquitination for each substrate?
Q: Which E3 ligase or ligases are recruited by LNX1p70, and is this recruitment required for endogenous ligand ubiquitination in neuronal cells?
Q: How do the abundance, localization, and partner networks of p80 and p70 differ across human tissues and cell states?
Experiment: Generate isogenic human cells expressing endogenous p80-only, p70-only, Zn-RING-Zn-inactive, PDZ-ligand-binding-defective, and dimer-interface-defective LNX1 alleles; combine ubiquitin-remnant proteomics with quantitative protein stability measurements to identify direct substrates and distinguish degradative from regulatory ubiquitination.
Hypothesis: The Zn-RING-Zn module is required for p80's intrinsic ubiquitination program, whereas PDZ interactions specify the substrate set and ubiquitin outcome.
Type: Isoform-resolved structure-function proteomics
Experiment: Reconstitute purified human LNX1p80 with alternative E2 enzymes and defined PDZ-recruited substrates, then measure ubiquitin linkage type, mono- versus polyubiquitination, and substrate turnover coupling.
Hypothesis: E2 selection and substrate context jointly determine whether LNX1p80 produces degradative chains or non-degradative ubiquitin signals.
Type: Biochemical ubiquitination reconstitution
Experiment: Map the endogenous LNX1p70 interactome in human neuronal cells by proximity labeling and affinity purification, prioritize candidate E3 ligases, and test each by depletion and rescue with catalytic and p70-interaction mutants.
Hypothesis: LNX1p70 promotes ligand ubiquitination by recruiting one or more specific E3 ligases rather than through residual intrinsic catalytic activity.
Type: Endogenous interactome mapping and genetic epistasis
Experiment: Endogenously tag each LNX1 isoform and quantify its expression, subcellular localization, and partner occupancy across epithelial and neuronal human cells under basal and signaling-stimulated conditions.
Hypothesis: p80 and p70 occupy distinct cellular niches that partition intrinsic E3-ligase and scaffold functions.
Type: Isoform-specific imaging and quantitative proteomics
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The endogenous, tissue-specific substrate hierarchy of LNX1p80 and the rules determining whether a recruited substrate undergoes degradative polyubiquitination, regulatory monoubiquitination, or another ubiquitin outcome remain unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: PDZ-dependent recruitment and ubiquitination are established for several substrates, including SRC, PPFIA1, KLHL11, KIF7, ERC2, and RHOC, but many reported partners come from interaction screens and only a subset has been validated as substrates.
Significance: Resolving this substrate-and-outcome code is necessary to distinguish LNX1's physiological proteostatic roles from its non-degradative signaling functions.
What would resolve it: Endogenous isoform-specific perturbation combined with ubiquitin-linkage, ubiquitin-remnant, protein-stability, and interaction proteomics across relevant cell types would identify direct substrates and classify their ubiquitin outcomes.
Provenance (the field's own admissions):
Gap: The identity of the E3 ligase or ligases recruited by RING-less LNX1p70, the ligand contexts in which recruitment occurs, and whether this indirect ubiquitination mechanism operates at endogenous abundance in vivo are unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: LNX1p70 lacks the catalytic RING region, retains the PDZ scaffold region, and can promote lower-level ligand ubiquitination in human cells; the published mechanism is explicitly a recruitment model rather than demonstrated intrinsic E3 catalysis by p70.
Significance: Identifying the recruited catalyst is essential for understanding the distinct biological role of the neuronal p70 isoform without misassigning p80's intrinsic ligase activity to it.
What would resolve it: Compare endogenous p70 interactomes with ubiquitination phenotypes after targeted depletion of candidate E3 ligases, followed by rescue with interaction-defective p70 and catalytically inactive candidate-E3 mutants.
Provenance (the field's own admissions):
Gap: Endogenous expression, localization, and partner occupancy of LNX1p80 versus LNX1p70 across human tissues and cell states are insufficiently resolved.
OPEN BIOLOGY CC_DARK
What is known: Human LNX1 is observed in the cytosol and at cell junctions, while p70 has been described as neuronal; current localization annotations do not distinguish the isoforms, and transferred synaptic biology is largely based on mouse evidence.
Significance: Isoform-resolved cellular context is required to connect the distinct catalytic and scaffold activities to physiological substrates and to evaluate proposed neuronal functions in humans.
What would resolve it: Introduce isoform-specific endogenous tags and use targeted transcript/protein quantification, imaging, and proximity labeling across epithelial and neuronal human models.
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