APLP1 is a neuronal single-pass type I membrane glycoprotein of the amyloid precursor protein family that is enriched at postsynaptic sites. At the cell surface, APLP1 forms homo- and heterocomplexes with APP-family proteins and promotes trans-cellular adhesion. Its extracellular region binds heparin and extracellular-matrix components and can regulate neurite outgrowth, while proteolytic processing produces soluble extracellular and intracellular fragments. The APLP1 E1 domain also binds the acidic C-terminus of alpha-synuclein with strong preference for the fibrillar over the monomeric state, and APLP1 has been proposed, in partnership with LAG3, to mediate neuronal uptake and cell-to-cell propagation of pathological alpha-synuclein. The identity of the neuronal alpha-synuclein fibril receptor is unsettled: FAM171A2 and LAG3 have been advanced as alternative or parallel mediators, and the LAG3 assignment is contested by work finding no LAG3 expression in human or murine neurons.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0007409 axonogenesis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: APLP1 has reported neurite outgrowth activity consistent with axonogenesis, but evidence is indirect. Reason: UniProt notes APLP1 can regulate neurite outgrowth through extracellular matrix binding. This supports a link to axonogenesis, but it is not the primary documented function. Supporting Evidence: file:genes/human/APLP1/APLP1-uniprot.txt Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I. |
| GO:0007417 central nervous system development | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: APLP1 is brain-enriched and localized to postsynaptic density, supporting CNS relevance but not specific developmental evidence. Reason: Expression and localization in cerebral cortex support CNS relevance, but the available references do not demonstrate a defined developmental role. Supporting Evidence: PMID:9521588 APLP1 is predominantly expressed in brain, particularly in the cerebral cortex postsynaptic density. |
| GO:0005794 Golgi apparatus | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Golgi association is limited to processing of the C30 fragment; not a primary localization. Reason: UniProt specifies C30 is processed in the Golgi complex, indicating a processing site rather than main localization of full-length APLP1. Supporting Evidence: file:genes/human/APLP1/APLP1-uniprot.txt [C30]: Cytoplasm. Note=C-terminally processed in the Golgi complex. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: APLP1 is a single-pass type I membrane protein at the cell surface. Reason: UniProt documents APLP1 as a cell membrane protein, consistent with its receptor-like adhesion roles. Supporting Evidence: file:genes/human/APLP1/APLP1-uniprot.txt Cell membrane; Single-pass type I membrane protein. |
| GO:0031694 alpha-2A adrenergic receptor binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: APLP1 directly binds the alpha2A-adrenergic receptor. Reason: The interaction is experimentally demonstrated but represents a specific regulatory interaction rather than the core APLP1 function. Supporting Evidence: PMID:16531006 This screen identified the amyloid precursor like protein 1 (APLP1), a homologue of the beta-amyloid precursor protein involved in Alzheimer's disease, as alpha2A-adrenergic receptor-binding protein. |
| GO:0031695 alpha-2B adrenergic receptor binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: APLP1 interacts with alpha2B-adrenergic receptor in vitro. Reason: The interaction is demonstrated but represents a specific partner interaction rather than core APLP1 activity. Supporting Evidence: PMID:16531006 GST affinity chromatography revealed that APLP1 specifically interacts with all three human alpha2-adrenergic receptor subtypes and deletion mutant analysis confined the APLP1 domain involved in binding to alpha2-adrenergic receptors to the 13 amino acid residues Ser599-Ala611 |
| GO:0031696 alpha-2C adrenergic receptor binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: APLP1 interacts with alpha2C-adrenergic receptor in vitro. Reason: The interaction is demonstrated but represents a specific partner interaction rather than core APLP1 activity. Supporting Evidence: PMID:16531006 GST affinity chromatography revealed that APLP1 specifically interacts with all three human alpha2-adrenergic receptor subtypes and deletion mutant analysis confined the APLP1 domain involved in binding to alpha2-adrenergic receptors to the 13 amino acid residues Ser599-Ala611 |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Cytoplasmic localization applies to the C30 fragment rather than the full-length membrane protein. Reason: UniProt specifies the processed C30 fragment is cytoplasmic, so this term is secondary to the membrane localization. Supporting Evidence: file:genes/human/APLP1/APLP1-uniprot.txt [C30]: Cytoplasm. Note=C-terminally processed in the Golgi complex. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane localization is a core cellular component annotation for APLP1. Reason: UniProt identifies APLP1 as a single-pass type I membrane protein at the cell membrane. Supporting Evidence: file:genes/human/APLP1/APLP1-uniprot.txt Cell membrane; Single-pass type I membrane protein. file:genes/human/APLP1/APLP1-deep-research-falcon.md APLP1 localizes predominantly to the neuronal cell surface compared with APP/APLP2, supporting a primary role at synapses (2018) |
| GO:0006897 endocytosis | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: APLP1 contains an NPXY motif involved in clathrin-mediated endocytosis, supporting endocytic trafficking. Reason: The NPXY motif implicated in clathrin-mediated endocytosis suggests APLP1 participates in endocytic trafficking but this is not its core function. Supporting Evidence: file:genes/human/APLP1/APLP1-uniprot.txt The NPXY site is also involved in clathrin-mediated endocytosis. |
| GO:0006915 apoptotic process | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: Evidence is fragment-specific and by-similarity; it does not support direct participation in apoptotic process for full-length APLP1. Reason: UniProt notes the C30 fragment enhances neuronal apoptosis by similarity, which is indirect and does not justify annotating APLP1 to apoptotic process. Supporting Evidence: file:genes/human/APLP1/APLP1-uniprot.txt The gamma-CTF peptide, C30, is a potent enhancer of neuronal apoptosis. |
| GO:0007155 cell adhesion | IEA GO_REF:0000043 | ACCEPT | Summary: APP family trans-interactions promote cell-cell adhesion, consistent with APLP1 synaptic adhesion. Reason: APLP1 forms homo/heterodimers that promote trans-cellular adhesion, supporting cell adhesion as a core function. Supporting Evidence: PMID:16193067 trans-interaction of APP family proteins promotes cell-cell adhesion in a homo- and heterotypic fashion |
| GO:0007399 nervous system development | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Neuronal expression supports nervous system relevance but not specific developmental evidence. Reason: APLP1 is predominantly expressed in brain and localized to postsynaptic density; developmental roles are plausible but not directly demonstrated here. Supporting Evidence: PMID:9521588 APLP1 is predominantly expressed in brain, particularly in the cerebral cortex postsynaptic density. |
| GO:0008201 heparin binding | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Structural evidence shows heparin binds the APLP1 E2 domain. Reason: Heparin binding is experimentally demonstrated but represents a specific biochemical interaction rather than the primary function. Supporting Evidence: PMID:21930949 crystal structure of a complex between heparin and the E2 domain of APLP1 |
| GO:0016020 membrane | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: Generic membrane term is redundant with the more specific plasma membrane annotation. Reason: APLP1 is a plasma membrane single-pass protein; the broad membrane term adds little value compared with GO:0005886. Supporting Evidence: file:genes/human/APLP1/APLP1-uniprot.txt Cell membrane; Single-pass type I membrane protein. |
| GO:0046872 metal ion binding | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: APLP1 binds zinc and copper via its extracellular domain. Reason: UniProt reports zinc and copper binding; this supports metal ion binding as a secondary molecular function. Supporting Evidence: file:genes/human/APLP1/APLP1-uniprot.txt Binds zinc and copper in the extracellular domain. |
| GO:0046914 transition metal ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Transition metal ion binding is supported by reported zinc/copper binding. Reason: Zinc and copper are transition metals; UniProt notes binding in the extracellular domain. Supporting Evidence: file:genes/human/APLP1/APLP1-uniprot.txt Binds zinc and copper in the extracellular domain. |
| GO:0048513 animal organ development | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: No direct evidence for animal organ development in the cited references. Reason: The available literature focuses on gene structure and brain expression, not organ development. Supporting Evidence: PMID:9521588 The genomic structure has been determined. |
| GO:0005515 protein binding | IPI PMID:16169070 A human protein-protein interaction network: a resource for ... | REMOVE | Summary: High-throughput Y2H interactome data are not specific and make protein binding uninformative here. Reason: The study is a large-scale yeast two-hybrid screen; without a defined partner, generic protein binding adds little curation value. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. Supporting Evidence: PMID:16169070 a protein matrix of 4456 baits and 5632 preys was screened by automated yeast two-hybrid |
| GO:0005515 protein binding | IPI PMID:16193067 Homo- and heterodimerization of APP family members promotes ... | MODIFY | Summary: APLP1 forms homo- and heterodimers; dimerization is more specific than generic protein binding. Reason: The study shows APLP1 participates in homo- and heterocomplex formation, which is best captured by a dimerization term. Proposed replacements: protein dimerization activity Supporting Evidence: PMID:16193067 all three paralogs are capable of forming homo- and heterocomplexes. |
| GO:0005515 protein binding | IPI PMID:21293490 Mediator is a transducer of amyloid-precursor-protein-depend... | UNDECIDED | Summary: The accessible abstract describes APP AICD/MED12 signaling but does not expose the APLP1-specific evidence underlying this experimental IPI annotation. Reason: The cached record is abstract-only. Because the curator had access to evidence not visible in the abstract, the APLP1 interaction cannot be confirmed or rejected from the locally available text. Supporting Evidence: PMID:21293490 In this study, we show that the AICD activates transcription by targeting MED12, an RNA polymerase II transcriptional Mediator subunit that is implicated in human cognitive development. |
| GO:0005515 protein binding | IPI PMID:23864651 The identification of novel proteins that interact with the ... | MODIFY | Summary: APLP1 interacts with the GLP-1 receptor; a receptor-binding term is more specific than generic protein binding. Reason: The study identifies APLP1 as a GLP-1 receptor interactor, indicating a signaling receptor binding role. Proposed replacements: signaling receptor binding Supporting Evidence: PMID:23864651 we then focused on 3 novel interactors, SLC15A4, APLP1, and AP2M1 |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Large-scale neurodegenerative interactome data are too nonspecific for a generic binding annotation. Reason: The study reports a systematic Y2H interaction network; without a defined partner, protein binding is uninformative. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. Supporting Evidence: PMID:32814053 generated by systematic yeast two-hybrid interaction screening |
| GO:0042802 identical protein binding | IPI PMID:16193067 Homo- and heterodimerization of APP family members promotes ... | MODIFY | Summary: APLP1 homodimerization is documented; a homodimerization term is more accurate. Reason: The study demonstrates APP family homo/heterocomplexes; for identical binding, homodimerization is more specific. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:16193067 all three paralogs are capable of forming homo- and heterocomplexes. |
| GO:0042802 identical protein binding | IPI PMID:21930949 Crystal structure of amyloid precursor-like protein 1 and he... | MODIFY | Summary: Heparin promotes APLP1 E2 homodimer formation, supporting homodimerization activity. Reason: Structural data indicate E2 domain dimerization; homodimerization activity captures this more specifically than identical protein binding. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:21930949 crystal structure of a complex between heparin and the E2 domain of APLP1 |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Golgi association reflects processing of C30 rather than main APLP1 localization. Reason: UniProt notes C30 is processed in the Golgi complex, implying a processing site. Supporting Evidence: file:genes/human/APLP1/APLP1-uniprot.txt [C30]: Cytoplasm. Note=C-terminally processed in the Golgi complex. |
| GO:0030198 extracellular matrix organization | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: APLP1 binds extracellular matrix components but is not shown to organize ECM. Reason: Binding to ECM components supports neurite outgrowth roles, not direct extracellular matrix organization. Supporting Evidence: file:genes/human/APLP1/APLP1-uniprot.txt Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I. |
| GO:0030900 forebrain development | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Forebrain development is not directly supported; only brain expression is reported. Reason: The cited reference reports expression in cerebral cortex but does not demonstrate a developmental role. Supporting Evidence: PMID:9521588 APLP1 is predominantly expressed in brain, particularly in the cerebral cortex postsynaptic density. |
| GO:0106072 negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway | IDA PMID:16531006 Interaction of the amyloid precursor like protein 1 with the... | KEEP AS NON CORE | Summary: APLP1 enhances agonist-mediated inhibition of adenylate cyclase downstream of alpha2A-adrenergic receptor signaling. Reason: The study reports increased norepinephrine-mediated inhibition of adenylate cyclase upon APLP1 coexpression, supporting a regulatory role in GPCR signaling. Supporting Evidence: PMID:16531006 cotransfection of alpha2A-adrenergic receptor and APLP1 into HEK293 cells significantly increased norepinephrine mediated inhibition of adenylate cyclase activity. |
| GO:0071874 cellular response to norepinephrine stimulus | IDA PMID:16531006 Interaction of the amyloid precursor like protein 1 with the... | KEEP AS NON CORE | Summary: APLP1 modulates cellular responses to norepinephrine via alpha2A-adrenergic receptor signaling. Reason: The norepinephrine response is documented in the same study but reflects a specific signaling context rather than a core APLP1 role. Supporting Evidence: PMID:16531006 cotransfection of alpha2A-adrenergic receptor and APLP1 into HEK293 cells significantly increased norepinephrine mediated inhibition of adenylate cyclase activity. |
| GO:0005886 plasma membrane | IDA PMID:16531006 Interaction of the amyloid precursor like protein 1 with the... | ACCEPT | Summary: APLP1 is a plasma membrane protein, consistent with receptor interactions in the study. Reason: Independent evidence establishes plasma membrane localization, aligning with the receptor interaction experiments. Supporting Evidence: file:genes/human/APLP1/APLP1-uniprot.txt Cell membrane; Single-pass type I membrane protein. PMID:16531006 Confocal laser microscopy showed that APLP1 causes a considerable shift of the alpha2A-adrenergic receptor localization from plasma membrane to intracellular compartments. |
| GO:0031694 alpha-2A adrenergic receptor binding | IPI PMID:16531006 Interaction of the amyloid precursor like protein 1 with the... | KEEP AS NON CORE | Summary: APLP1 binds alpha2A-adrenergic receptor. Reason: The interaction is experimentally shown but represents a specific regulatory partner interaction rather than a core function. Supporting Evidence: PMID:16531006 This screen identified the amyloid precursor like protein 1 (APLP1), a homologue of the beta-amyloid precursor protein involved in Alzheimer's disease, as alpha2A-adrenergic receptor-binding protein. |
| GO:0031695 alpha-2B adrenergic receptor binding | IPI PMID:16531006 Interaction of the amyloid precursor like protein 1 with the... | KEEP AS NON CORE | Summary: APLP1 binds alpha2B-adrenergic receptor. Reason: The interaction is documented but is a specific partner interaction rather than a core APLP1 activity. Supporting Evidence: PMID:16531006 GST affinity chromatography revealed that APLP1 specifically interacts with all three human alpha2-adrenergic receptor subtypes and deletion mutant analysis confined the APLP1 domain involved in binding to alpha2-adrenergic receptors to the 13 amino acid residues Ser599-Ala611 |
| GO:0031696 alpha-2C adrenergic receptor binding | IPI PMID:16531006 Interaction of the amyloid precursor like protein 1 with the... | KEEP AS NON CORE | Summary: APLP1 binds alpha2C-adrenergic receptor. Reason: The interaction is documented but is a specific partner interaction rather than a core APLP1 activity. Supporting Evidence: PMID:16531006 GST affinity chromatography revealed that APLP1 specifically interacts with all three human alpha2-adrenergic receptor subtypes and deletion mutant analysis confined the APLP1 domain involved in binding to alpha2-adrenergic receptors to the 13 amino acid residues Ser599-Ala611 |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:16531006 Interaction of the amyloid precursor like protein 1 with the... | UNDECIDED | Summary: The study reports intracellular relocalization of alpha2A receptors, but perinuclear localization is not explicitly documented. Reason: The abstract indicates a shift to intracellular compartments without specifying perinuclear localization; full-text evidence is needed. Supporting Evidence: PMID:16531006 Confocal laser microscopy showed that APLP1 causes a considerable shift of the alpha2A-adrenergic receptor localization from plasma membrane to intracellular compartments. |
| GO:0009887 animal organ morphogenesis | TAS PMID:9521588 Structure of the human amyloid-precursor-like protein gene A... | MARK AS OVER ANNOTATED | Summary: The cited reference is a gene structure study and does not support organ morphogenesis. Reason: PMID:9521588 focuses on genomic structure and expression; it does not provide morphogenesis evidence. Supporting Evidence: PMID:9521588 the genomic structure has been determined |
| GO:0005604 basement membrane | TAS PMID:9521588 Structure of the human amyloid-precursor-like protein gene A... | MARK AS OVER ANNOTATED | Summary: Basement membrane association is speculative in the cited reference. Reason: The paper only notes a proposed interference with basement membrane assembly as a rationale for candidacy, not direct evidence. Supporting Evidence: PMID:9521588 the proposed interference of amyloid with basement membrane assembly |
| GO:0007399 nervous system development | TAS PMID:9521588 Structure of the human amyloid-precursor-like protein gene A... | KEEP AS NON CORE | Summary: Brain-enriched expression suggests nervous system relevance but does not directly demonstrate developmental function. Reason: Expression in cerebral cortex supports nervous system relevance; developmental evidence is indirect. Supporting Evidence: PMID:9521588 APLP1 is predominantly expressed in brain, particularly in the cerebral cortex postsynaptic density. |
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Download this section (compressed HTML)Q: Does APLP1 support neuronal uptake and propagation of alpha-synuclein fibrils in the absence of LAG3? The published in vivo rescue used an Aplp1/Lag3 double knockout, so the APLP1-only contribution has not been isolated.
Suggested experts: Mao X, Dawson TM
Q: Given that LAG3 was not detected in human or murine neurons, is the APLP1-LAG3 complex the operative species in neurons, or is the APLP1 contribution LAG3-independent?
Suggested experts: Emmenegger M, Aguzzi A
Q: Are FAM171A2, APLP1 and LAG3 redundant, sequential or cell-type-restricted entry routes for alpha-synuclein fibrils, and do they compete for the same acidic C-terminal epitope of alpha-synuclein?
Suggested experts: Yu JT, Liu C
Q: Should GO annotate APLP1 with an alpha-synuclein/amyloid-fibril binding molecular function, or is the evidence still too dependent on a single group and on LAG3 co-expression?
Experiment: Measure alpha-synuclein preformed fibril binding and internalization in primary neurons from Aplp1 single-knockout, Lag3 single-knockout and double-knockout mice, with quantitative surface-binding (Kd) and Rab7-normalized uptake readouts, so the APLP1-only contribution is separated from the complex.
Hypothesis: APLP1 binds and internalizes alpha-synuclein fibrils independently of LAG3.
Type: genetic dissection / cellular uptake assay
Experiment: Perform competition binding with purified APLP1 E1, LAG3 D1 and FAM171A2 extracellular domain 1 against alpha-synuclein fibrils, including C-terminally truncated and pS129 fibrils, and test whether one ectodomain displaces another.
Hypothesis: APLP1, LAG3 and FAM171A2 engage the same acidic C-terminal epitope of alpha-synuclein and therefore compete.
Type: competitive biophysical binding
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: It is undetermined whether APLP1 acts as a bona fide neuronal receptor for fibrillar alpha-synuclein in its own right, or only as an obligate partner within an APLP1-LAG3 complex. No binding constant, stoichiometry or uptake requirement has been reported for APLP1 in the absence of LAG3, and the in vivo genetic protection was obtained from an Aplp1/Lag3 double knockout rather than from an Aplp1 single knockout.
OPEN BIOLOGYONTOLOGY MF_DARK
What is known: Firmly established: the isolated APLP1 E1 domain binds the acidic C-terminus of alpha-synuclein, strongly preferring the fibrillar over the monomeric state, by an electrostatic mechanism shared with LAG3 D1; and combined Aplp1/Lag3 deletion protects mouse dopaminergic neurons from alpha-synuclein preformed fibrils.
Significance: Anti-LAG3 antibodies are being pursued therapeutically on the strength of this mechanism, and the partner on which the APLP1 model depends has itself been reported absent from human and murine neurons. Which protein actually performs the uptake step determines the target.
What would resolve it: Aplp1 single-knockout (rather than double-knockout) neuronal uptake, seeding and spreading assays; quantitative affinity and internalization measurements for APLP1 alone in LAG3-null neurons; and replication outside the originating laboratories. GO additionally provides no molecular-function term for alpha-synuclein or amyloid-fibril binding, so even a resolved result could not be expressed at the appropriate specificity today.
Provenance (the field's own admissions):
Proposed term (ontology gap):
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