LNPEP encodes a zinc-dependent M1 aminopeptidase that is synthesized as a single-pass type-II membrane protein with a short cytosolic N-terminal region and a lumen-facing or extracellular catalytic domain. It removes N-terminal residues from peptide hormones and neuropeptides, including oxytocin, vasopressin, angiotensin III, Met-enkephalin, and dynorphin. Full-length LNPEP cycles between intracellular vesicles and the plasma membrane, including insulin-responsive vesicles and antigen-processing endosomes, where it helps trim peptide precursors for MHC class I cross-presentation. Proteolytic release of its ectodomain produces a soluble pregnancy-serum aminopeptidase. Its cytosolic tail also participates in regulated vesicle sorting, although the physiological mechanism and conservation of this noncatalytic role in human cells remain incompletely defined.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0010813 neuropeptide catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: LNPEP directly degrades neuronal peptides, making neuropeptide catabolism a core physiological use of its aminopeptidase activity. Reason: Human P-LAP/LNPEP protein was detected in brain and neuronal cells and hydrolyzed Met-enkephalin and dynorphin; the phylogenetic annotation is independently supported by direct human evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002609779 SUPPORTS TRANSFER RGD:621752 SUPPORTS TRANSFER Supporting Evidence: PMID:11389728 P-LAP was shown to degrade several bioactive neuropeptides such as Met-enkephalin and dynorphin A (1-8). |
| GO:0006508 proteolysis | IBA GO_REF:0000033 | MODIFY | Summary: The broad proteolysis annotation captures LNPEP hydrolysis but is less precise than peptide catabolism. Reason: LNPEP removes single N-terminal residues from peptide hormones, neuropeptides, and antigenic peptide precursors; GO:0043171 describes this substrate scale more accurately than generic proteolysis. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: FB:FBgn0285963 SUPPORTS TRANSFER MGI:MGI:106645 SUPPORTS TRANSFER MGI:MGI:1933403 SUPPORTS TRANSFER MGI:MGI:5000466 SUPPORTS TRANSFER PANTHER:PTN000164251 SUPPORTS TRANSFER RGD:2991 SUPPORTS TRANSFER RGD:621228 SUPPORTS TRANSFER SGD:S000001089 SUPPORTS TRANSFER UniProtKB:Q7Q2T8 SUPPORTS TRANSFER UniProtKB:Q9NZ08 SUPPORTS TRANSFER Proposed replacements: peptide catabolic process Supporting Evidence: PMID:1731608 We also examined the hydrolytic activity of P-LAP using naturally occurring peptide hormones and found that the enzyme hydrolyzed oxytocin, vasopressin, and angiotensin III. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Plasma membrane is a bona fide execution site for membrane-bound LNPEP after regulated vesicle translocation. Reason: Direct human endothelial and adipocyte studies show LNPEP/oxytocinase translocation to the cell surface or plasma membrane, corroborating the phylogenetic inference. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:2387123 SUPPORTS TRANSFER PANTHER:PTN002609779 SUPPORTS TRANSFER RGD:621752 SUPPORTS TRANSFER UniProtKB:Q9UIQ6 SUPPORTS TRANSFER Supporting Evidence: PMID:11108258 In summary, our findings provide clear evidence that OT triggers directly OTase translocation in human umbilical vascular endothelial cells via a protein kinase C-dependent pathway coupled to OTR. |
| GO:0008217 regulation of blood pressure | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: LNPEP can influence blood-pressure physiology through metabolism and ligand binding in the renin-angiotensin system, but this is a downstream context rather than its defining activity. Reason: Human LNPEP hydrolyzes angiotensin III and is the high-affinity angiotensin IV binding site; organismal blood-pressure regulation is therefore plausible but secondary to its metalloaminopeptidase activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002609779 SUPPORTS TRANSFER RGD:621752 SUPPORTS TRANSFER Supporting Evidence: PMID:11707427 We have therefore demonstrated that the AT(4) receptor is IRAP and propose that AT(4) receptor ligands may exert their effects by inhibiting the catalytic activity of IRAP thereby extending the half-life of its neuropeptide substrates. |
| GO:0070006 metalloaminopeptidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Zinc-dependent metalloaminopeptidase activity is LNPEP's core catalytic function. Reason: Purified human placental enzyme hydrolyzes N-terminal residues from oxytocin, vasopressin, and angiotensin III, while the human sequence contains the defining M1 zinc-metallopeptidase motifs. Propagation Review Root cause: NO FAILURE CORE Sources checked: CGD:CAL0000186164 SUPPORTS TRANSFER PANTHER:PTN000164250 SUPPORTS TRANSFER SGD:S000001640 SUPPORTS TRANSFER UniProtKB:Q07075 SUPPORTS TRANSFER WB:WBGene00003914 SUPPORTS TRANSFER WB:WBGene00011587 SUPPORTS TRANSFER Supporting Evidence: PMID:1731608 By comparing P-LAP activity with cystine aminopeptidase activity, we concluded that both activities were shared by the same molecule. |
| GO:0002474 antigen processing and presentation of peptide antigen via MHC class I | IEA GO_REF:0000117 | ACCEPT | Summary: LNPEP participates in MHC-I cross-presentation by trimming antigenic peptide precursors in an endosomal compartment. Reason: Human dendritic-cell localization and interaction data, together with loss-of-function experiments, directly support an MHC-I antigen-processing role; the broad parent term avoids overcommitting to one transport route. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00088849 SUPPORTS TRANSFER Supporting Evidence: PMID:19498108 We found a role for peptide trimming by insulin-regulated aminopeptidase (IRAP) in cross-presentation. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Extracellular localization applies to the proteolytically shed pregnancy-serum form of LNPEP. Reason: LNPEP is synthesized as a type-II membrane enzyme and released into blood under physiological conditions; this annotation does not imply that the intact membrane form is extracellularly soluble. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0243 SUPPORTS TRANSFER Supporting Evidence: PMID:8550619 These results suggest that the enzyme is synthesized as an integral membrane protein and is released into blood under some physiological conditions. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Plasma-membrane localization is directly established for human LNPEP and conserved in the mouse ortholog. Reason: Human adipocytes and endothelial cells show stimulus-regulated LNPEP recruitment to the plasma membrane, fully corroborating the combined electronic mapping. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00027801 SUPPORTS TRANSFER UniProtKB:Q8C129 SUPPORTS TRANSFER ensembl:ENSMUSP00000036998 SUPPORTS TRANSFER UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER Supporting Evidence: PMID:11701721 We conclude that in human adipocytes: 1) IRAP is expressed and translocates to PM in response to insulin; |
| GO:0006508 proteolysis | IEA GO_REF:0000002 | MODIFY | Summary: Generic proteolysis is true but less informative than peptide catabolism for this exopeptidase. Reason: The M1 peptidase domain releases N-terminal residues from peptides rather than carrying out indiscriminate bulk protein degradation. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR001930 SUPPORTS TRANSFER Proposed replacements: peptide catabolic process Supporting Evidence: PMID:1731608 We also examined the hydrolytic activity of P-LAP using naturally occurring peptide hormones and found that the enzyme hydrolyzed oxytocin, vasopressin, and angiotensin III. |
| GO:0008237 metallopeptidase activity | IEA GO_REF:0000120 | MODIFY | Summary: Metallopeptidase activity is correct but the metalloaminopeptidase child term captures LNPEP's exopeptidase specificity. Reason: Human biochemical evidence and the M1 aminopeptidase domain support GO:0070006 rather than the generic metallopeptidase parent. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00027402 SUPPORTS TRANSFER InterPro:IPR014782 SUPPORTS TRANSFER Proposed replacements: metalloaminopeptidase activity Supporting Evidence: PMID:1731608 By comparing P-LAP activity with cystine aminopeptidase activity, we concluded that both activities were shared by the same molecule. |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Zinc binding is a real catalytic cofactor feature but is not a distinct core function beyond metalloaminopeptidase activity. Reason: The human sequence contains the canonical gluzincin coordination element, supporting zinc binding while making the catalytic GO:0070006 annotation more informative. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: InterPro:IPR014782 SUPPORTS TRANSFER Supporting Evidence: PMID:9177475 Oxytocinase is a type II integral membrane protein of 1025 amino acid residues, consisting of an acidic intracellular region of 110 amino acids followed by a hydrophobic transmembrane segment of 22 residues and 893 extracellular residues containing the characteristic Zn2+ coordination sequence element His-Glu-Xaa-Xaa-His-(18 residues)-Glu found in gluzincins. |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000117 | MODIFY | Summary: LNPEP is an integral component of cytoplasmic vesicle membranes, not a soluble vesicle-lumen protein. Reason: The broad vesicle location is directionally correct, but type-II topology and direct endosomal/GLUT4-vesicle evidence support the membrane-specific child term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00027190 SUPPORTS SOURCE BUT NOT TARGET Proposed replacements: cytoplasmic vesicle membrane Supporting Evidence: PMID:19498108 In human dendritic cells, IRAP was localized to a Rab14+ endosomal storage compartment in which it interacted with MHC class I molecules. |
| GO:0005515 protein binding | IPI PMID:12080061 Identification of a tankyrase-binding motif shared by IRAP, ... | MARK AS OVER ANNOTATED | Summary: LNPEP contains a validated tankyrase-binding motif, but generic protein binding does not capture the informative relationship. Reason: PMID:12080061 directly supports interaction with TNKS2 through an RXXPDG motif; no current GO term specifically represents tankyrase binding, so the physical interaction should remain in evidence notes rather than as generic protein binding. Supporting Evidence: PMID:12080061 Herein we describe a novel RXXPDG motif shared by IRAP, TAB182, and human TRF1 that mediates their binding to tankyrases. |
| GO:0005515 protein binding | IPI PMID:22153077 Structural basis and sequence rules for substrate recognitio... | MARK AS OVER ANNOTATED | Summary: Structural work corroborates LNPEP recognition by TNKS2, but generic protein binding is uninformative. Reason: The IPI edge is biologically plausible and consistent with the established RXXPDG tankyrase-binding motif, yet GO:0005515 does not describe a functional activity and no tankyrase-specific binding term exists. Supporting Evidence: PMID:12080061 Tankyrase-1 and -2 are closely related poly(ADP-ribose) polymerases that use an ankyrin-repeat domain to bind diverse proteins, including TRF (telomere-repeat binding factor)-1, IRAP (insulin-responsive aminopeptidase), and TAB182 (182-kDa tankyrase-binding protein). |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: The three consolidated HI-II-14 binary-interaction edges are real screen provenance but do not define LNPEP function. Reason: A systematic Y2H map supports the reported physical edges to TCF4, REL, and FATE1, but no focused validation or shared functional consequence justifies generic protein binding as a useful GO function. Supporting Evidence: PMID:25416956 Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions. |
| GO:0005515 protein binding | IPI Q9UIQ6-2 PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: HuRI detected 23 binary partners for the tested Q9UIQ6-2 construct, but the aggregate generic-binding annotation has no coherent functional interpretation. Reason: Preserve the isoform and all tested partner accessions as source provenance. The Y2H edges are not evidence that the short N-terminal deletion is functionally unique, that one stable complex exists, or that generic protein binding is a core activity. Supporting Evidence: PMID:32296183 While HuRI displays highly significant overlap with known functional relationships, the cellular function of most individual PPIs remains to be elucidated. |
| GO:0004177 aminopeptidase activity | IEA GO_REF:0000120 | MODIFY | Summary: Aminopeptidase activity is correct but can be specified as zinc-dependent metalloaminopeptidase activity. Reason: Direct human biochemistry establishes N-terminal peptide hydrolysis by a zinc M1 aminopeptidase, supporting GO:0070006. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: ARBA:ARBA00028139 SUPPORTS TRANSFER UniProtKB:Q8C129 SUPPORTS TRANSFER ensembl:ENSMUSP00000036998 SUPPORTS TRANSFER Proposed replacements: metalloaminopeptidase activity Supporting Evidence: PMID:1731608 By comparing P-LAP activity with cystine aminopeptidase activity, we concluded that both activities were shared by the same molecule. |
| GO:0016020 membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Broad membrane localization is correct for the intact type-II LNPEP protein and is complemented by more specific source annotations. Reason: LNPEP cycles between intracellular vesicle membranes and the plasma membrane. The broad term is faithful to the orthology source and does not need replacement because both specific locations are already represented separately. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8C129 SUPPORTS TRANSFER ensembl:ENSMUSP00000036998 SUPPORTS TRANSFER Supporting Evidence: PMID:11701721 Therefore, we studied subcellular localization of GLUT4 and insulin-regulated aminopeptidase (IRAP; also referred to as vp165 or gp160), which is a constituent of GLUT4 vesicles and also translocates to PM in response to insulin. |
| GO:0030659 cytoplasmic vesicle membrane | IEA GO_REF:0000107 | ACCEPT | Summary: Cytoplasmic vesicle membrane is a core location for intact LNPEP in GLUT4-storage and endosomal antigen-processing compartments. Reason: Human adipocyte and dendritic-cell studies directly place LNPEP in membrane-bounded intracellular vesicles, corroborating orthology-based transfer. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8C129 SUPPORTS TRANSFER ensembl:ENSMUSP00000036998 SUPPORTS TRANSFER Supporting Evidence: PMID:19498108 In human dendritic cells, IRAP was localized to a Rab14+ endosomal storage compartment in which it interacted with MHC class I molecules. |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Perinuclear localization describes a contextual pool of LNPEP-containing storage vesicles rather than a distinct core function. Reason: GLUT4 storage vesicles can be sequestered in perinuclear compartments, but LNPEP also occupies other endosomes and the plasma membrane; retain the transferred location with that scope. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8C129 SUPPORTS TRANSFER ensembl:ENSMUSP00000036998 SUPPORTS TRANSFER Supporting Evidence: PMID:17059388 In the basal state, most GSVs are sequestered in perinuclear and other cytosolic compartments. |
| GO:0120163 negative regulation of cold-induced thermogenesis | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Mouse loss-of-function increases basal energy expenditure but does not support a specific negative role in cold-induced thermogenesis. Reason: PMID:25534853 measured basal whole-body oxygen consumption rather than a cold challenge and explicitly reports that adaptive thermogenesis was not impaired. The transferred term is therefore over-specific for the mouse phenotype and should not define human LNPEP function. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8C129 SUPPORTS TRANSFER ensembl:ENSMUSP00000036998 SUPPORTS TRANSFER Supporting Evidence: PMID:25534853 Indirect calorimetry demonstrated that whole-body oxygen consumption rates were significantly higher in IRAP(-/-) mice by 18% with mild hyperthermia. |
| GO:0000209 protein polyubiquitination | TAS Reactome:R-HSA-983168 | REMOVE | Summary: LNPEP is not part of the ubiquitin-conjugation machinery in this Reactome pathway. Reason: Reactome appears to have propagated LNPEP from a misassembled cytosolic aminopeptidase set into an upstream ubiquitination pathway. LNPEP acts downstream by trimming peptide precursors and is neither an E1, E2, E3, nor proteasome component. Supporting Evidence: Reactome:R-HSA-983168 This process involves three classes of enzyme, an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase. PMID:19498108 We propose the existence of two pathways for proteasome-dependent cross-presentation in which final peptide trimming involves IRAP in endosomes and involves the related aminopeptidases in the endoplasmic reticulum. |
| GO:0002480 antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-independent | TAS Reactome:R-HSA-1236977 | MODIFY | Summary: LNPEP supports exogenous-antigen cross-presentation, but TAP independence is not established and the demonstrated route requires proteasomes. Reason: The broader exogenous-peptide MHC-I presentation term captures the experimentally supported process without importing Reactome's distinct vacuolar/TAP-independent route. Proposed replacements: antigen processing and presentation of exogenous peptide antigen via MHC class I Supporting Evidence: PMID:19498108 We propose the existence of two pathways for proteasome-dependent cross-presentation in which final peptide trimming involves IRAP in endosomes and involves the related aminopeptidases in the endoplasmic reticulum. |
| GO:0004177 aminopeptidase activity | EXP PMID:11062501 Two new proteases in the MHC class I processing pathway. | TOO GENERAL | Summary: True but broad: entailed by metalloaminopeptidase activity, kept in this review. Reason: The claim is true: metalloaminopeptidase activity, kept in this review, entails this term. The evidence behind this row is about a different aminopeptidase; that is recorded in source_defects, not grounds for REMOVE, which judges the claim. |
| GO:0004177 aminopeptidase activity | EXP PMID:19498108 IRAP identifies an endosomal compartment required for MHC cl... | MODIFY | Summary: IRAP/LNPEP aminopeptidase activity performs final antigenic-peptide trimming in endosomes, but the zinc-dependent term is more specific. Reason: The human dendritic-cell study identifies IRAP-dependent peptide trimming during cross-presentation, while direct human biochemistry establishes that LNPEP is specifically a metalloaminopeptidase rather than only a generic aminopeptidase. Proposed replacements: metalloaminopeptidase activity Supporting Evidence: PMID:19498108 We found a role for peptide trimming by insulin-regulated aminopeptidase (IRAP) in cross-presentation. |
| GO:0004177 aminopeptidase activity | EXP PMID:19918052 Different cross-presentation pathways in steady-state and in... | MODIFY | Summary: The paper supports context-dependent IRAP aminopeptidase action in inflammatory dendritic-cell cross-presentation, but the zinc-dependent term is more specific. Reason: The study shows that IRAP-dependent trimming is biologically used in inflammatory monocyte-derived dendritic cells, while direct human biochemistry supports the more informative metalloaminopeptidase term. Proposed replacements: metalloaminopeptidase activity Supporting Evidence: PMID:19918052 However, cross-presentation was impaired in moDC deficient in IRAP or MR, confirming the role of these two molecules in inflammatory DC. |
| GO:0004177 aminopeptidase activity | EXP PMID:9668046 Interferon-gamma can stimulate post-proteasomal trimming of ... | TOO GENERAL | Summary: True but broad: entailed by metalloaminopeptidase activity, kept in this review. Reason: The claim is true: metalloaminopeptidase activity, kept in this review, entails this term. The evidence behind this row is about a different aminopeptidase; that is recorded in source_defects, not grounds for REMOVE, which judges the claim. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Plasma-membrane localization in the hippocampal formation is a defensible orthology transfer and agrees with human neuronal evidence. Reason: The exact source is rat IRAP, while human brain and neuronal cells contain membrane-bound LNPEP that can translocate from intracellular vesicles to the cell surface; the extension records the transferred anatomical context rather than claiming human IDA. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P97629 SUPPORTS TRANSFER Supporting Evidence: PMID:11389728 In contrast with the placenta where a significant portion of P-LAP is released, the enzyme was localized in the membrane fraction in brain and PC12 cells and no soluble form of the enzyme was detected. |
| GO:0005886 plasma membrane | IDA PMID:11108258 Oxytocin stimulates the translocation of oxytocinase of huma... | ACCEPT | Summary: Human endothelial cells directly show stimulus-driven LNPEP/oxytocinase recruitment to the cell surface. Reason: The cellular assay directly supports plasma-membrane localization and regulated cycling between intracellular stores and the surface. Supporting Evidence: PMID:11108258 In summary, our findings provide clear evidence that OT triggers directly OTase translocation in human umbilical vascular endothelial cells via a protein kinase C-dependent pathway coupled to OTR. |
| GO:0120163 negative regulation of cold-induced thermogenesis | ISS PMID:25534853 IRAP deficiency attenuates diet-induced obesity in mice thro... | MARK AS OVER ANNOTATED | Summary: Mouse knockout data show elevated basal energy expenditure but do not establish negative regulation of cold-induced thermogenesis. Reason: PMID:25534853 did not use a cold challenge and explicitly states that adaptive thermogenesis was not impaired. The direction-specific cold-thermogenesis term overinterprets a basal mouse metabolic phenotype. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:Q8C129 SUPPORTS TRANSFER Supporting Evidence: PMID:25534853 Indirect calorimetry demonstrated that whole-body oxygen consumption rates were significantly higher in IRAP(-/-) mice by 18% with mild hyperthermia. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: High-throughput membrane proteomics is consistent with LNPEP's experimentally established type-II membrane topology. Reason: The HDA row is broad but appropriate to the assay resolution; independent human sequence and localization evidence confirms that intact LNPEP is membrane embedded. Supporting Evidence: PMID:9177475 Oxytocinase is a type II integral membrane protein of 1025 amino acid residues, consisting of an acidic intracellular region of 110 amino acids followed by a hydrophobic transmembrane segment of 22 residues and 893 extracellular residues containing the characteristic Zn2+ coordination sequence element His-Glu-Xaa-Xaa-His-(18 residues)-Glu found in gluzincins. |
| GO:0005765 lysosomal membrane | HDA PMID:17897319 Integral and associated lysosomal membrane proteins. | KEEP AS NON CORE | Summary: Lysosomal-membrane detection is plausible but represents a context-specific proteomic pool rather than LNPEP's principal execution site. Reason: The curator had access to the placental lysosome proteomics dataset, while the cached abstract does not expose the individual LNPEP row. Retain the HDA localization without elevating it over the stronger plasma-, early-endosome-, and storage-vesicle-membrane evidence. Supporting Evidence: PMID:17897319 In membranes purified from placental lysosomes, we identified 58 proteins, known to reside at least partially in the lysosomal membrane. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-983162 | REMOVE | Summary: Full-length LNPEP is not a soluble cytosolic aminopeptidase. Reason: Reactome's cytosolic reaction lists TPP2, PSA, bleomycin hydrolase, and LAP and appears to include Q9UIQ6 through a historical leucine-aminopeptidase name collision. LNPEP residues 1-110 face the cytosol, but the intact protein is membrane embedded; topology does not justify whole-protein cytosol localization. Supporting Evidence: Reactome:R-HSA-983162 Some peptides generated by the 26S proteasome are too long to bind to MHC class I molecules. These N-terminal extended precursor peptides may be trimmed by cytosolic aminopeptidases, such as Tripeptidyl peptidase II (TPP2), puromycin-sensitive aminopeptidase (PSA), bleomycin hydrolase (BH), and leucine aminopeptidase (LAP). PMID:9177475 Oxytocinase is a type II integral membrane protein of 1025 amino acid residues, consisting of an acidic intracellular region of 110 amino acids followed by a hydrophobic transmembrane segment of 22 residues and 893 extracellular residues containing the characteristic Zn2+ coordination sequence element His-Glu-Xaa-Xaa-His-(18 residues)-Glu found in gluzincins. |
| GO:0031905 early endosome lumen | TAS Reactome:R-HSA-1236954 | MODIFY | Summary: LNPEP occupies the early-endosome membrane, with its catalytic domain exposed to the lumen; the whole protein is not a lumenal component. Reason: Reactome's own pathway description places IRAP in early/recycling endosomes, while type-II topology requires the membrane-specific component term GO:0031901. Proposed replacements: early endosome membrane Supporting Evidence: Reactome:R-HSA-1236954 IRAP is detected predominantly in the early and recycling endosome fractions. PMID:19498108 In human dendritic cells, IRAP was localized to a Rab14+ endosomal storage compartment in which it interacted with MHC class I molecules. |
| GO:0004177 aminopeptidase activity | TAS PMID:15691326 Regulation of the human leukocyte-derived arginine aminopept... | TOO GENERAL | Summary: True but broad: entailed by metalloaminopeptidase activity, kept in this review. Reason: The claim is true: metalloaminopeptidase activity, kept in this review, entails this term. This row's reference does not establish it; that is recorded in source_defects, not grounds for REMOVE, which judges the claim. |
| GO:0006508 proteolysis | TAS PMID:8550619 Human placental leucine aminopeptidase/oxytocinase. A new me... | MODIFY | Summary: Peptide catabolism is a more accurate process term than generic proteolysis for LNPEP's N-terminal exopeptidase activity. Reason: The source paper describes degradation of oxytocin and vasopressin by a zinc aminopeptidase, supporting GO:0043171. Proposed replacements: peptide catabolic process Supporting Evidence: PMID:8550619 P-LAP degrades several peptide hormones such as oxytocin and vasopresin, suggesting a role in maintaining homeostasis during pregnancy. |
| GO:0007267 cell-cell signaling | TAS PMID:8550619 Human placental leucine aminopeptidase/oxytocinase. A new me... | MODIFY | Summary: The connection to intercellular signaling is through peptide-signal degradation, which is captured more directly by neuropeptide catabolism. Reason: Generic cell-cell signaling makes LNPEP appear to be a signaling ligand or core transducer; its demonstrated role is enzymatic termination or modulation of peptide signals. Proposed replacements: neuropeptide catabolic process Supporting Evidence: PMID:11389728 P-LAP was shown to degrade several bioactive neuropeptides such as Met-enkephalin and dynorphin A (1-8). |
| GO:0007565 female pregnancy | TAS PMID:8550619 Human placental leucine aminopeptidase/oxytocinase. A new me... | KEEP AS NON CORE | Summary: LNPEP contributes to pregnancy physiology by degrading oxytocin and vasopressin, but female pregnancy is a broad downstream context. Reason: Placental expression, gestational serum increase, and direct hormone hydrolysis make the process defensible; the defining molecular activity remains metalloaminopeptidase activity. Supporting Evidence: PMID:1731608 These results suggest that P-LAP shows oxytocinase activity and plays an important role in the regulation of the plasma level of these hormones during pregnancy. |
| GO:0008237 metallopeptidase activity | TAS PMID:9177475 The complete amino acid sequence of human placental oxytocin... | MODIFY | Summary: Metallopeptidase activity is correct but GO:0070006 specifies LNPEP's aminopeptidase mechanism. Reason: The human sequence contains the gluzincin metal-coordination and GAMEN aminopeptidase motifs, and direct biochemical work establishes N-terminal peptide hydrolysis. Proposed replacements: metalloaminopeptidase activity Supporting Evidence: PMID:9177475 A conserved sequence element, the GAMEN motif, which distinguishes the aminopeptidase family among gluzincins from other gluzincins, has been identified. |
| GO:0008270 zinc ion binding | TAS PMID:8550619 Human placental leucine aminopeptidase/oxytocinase. A new me... | KEEP AS NON CORE | Summary: Zinc binding is an authentic catalytic feature but is redundant as a standalone core function. Reason: The source sequence establishes the HEXXH zinc-metallopeptidase motif; GO:0070006 is the biologically informative catalytic annotation. Supporting Evidence: PMID:8550619 The predicted P-LAP contains the HEXXH consensus sequence of zinc metallopeptidases, indicating that the enzyme belongs to this family, which includes aminopeptidase N and aminopeptidase A. |
| GO:0032593 insulin-responsive compartment | IDA PMID:11701721 Adipocytes exhibit abnormal subcellular distribution and tra... | NEW | Summary: Human adipocyte fractionation directly places LNPEP/IRAP in insulin-responsive GLUT4-containing membrane vesicles that translocate to the plasma membrane. Reason: GO:0032593 explicitly describes the GLUT4-, IRAP-, and VAMP2-enriched insulin-responsive compartment, a central localization absent from the source GOA set. Supporting Evidence: PMID:11701721 We conclude that in human adipocytes: 1) IRAP is expressed and translocates to PM in response to insulin; 2) GLUT4 depletion involves all membrane subfractions in type 2 diabetes, although cellular levels of IRAP are normal; and 3) in type 2 diabetes, IRAP accumulates in membrane vesicles cofractionating with HDM and PM under basal conditions, and insulin-mediated recruitment to PM is impaired. |
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Download this section (compressed HTML)Q: Which endogenous cytosolic-tail interactions and trafficking motifs make LNPEP necessary for formation or retention of insulin-responsive GLUT4 vesicles in human adipocytes?
Suggested experts: adipocyte membrane-trafficking specialists, insulin-signaling biologists
Q: Which peptide-import machinery and dendritic-cell activation states determine whether LNPEP-dependent endosomal trimming changes the human MHC-I immunopeptidome?
Suggested experts: antigen cross-presentation specialists, immunopeptidomics researchers
Q: Do Q9UIQ6-1, Q9UIQ6-2, and Q9UIQ6-3 differ in localization or substrate access, and which protease releases the pregnancy-serum ectodomain?
Suggested experts: placental protease specialists, aminopeptidase structural biologists
Experiment: Generate isogenic human adipocytes carrying endogenous dileucine-, tankyrase- motif, catalytic-site, or tail-deletion edits. Compare GLUT4-vesicle proteomics, live-cell exocytosis, glucose uptake, and rescue with expression-matched LNPEP constructs.
Hypothesis: LNPEP's cytosolic sorting motifs, rather than its aminopeptidase active site, are required to retain GLUT4 in insulin-responsive vesicles in human adipocytes.
Type: endogenous structure-function editing and vesicle-trafficking assay
Experiment: Acutely degrade LNPEP in primary human conventional and inflammatory dendritic cells with or without TAP1/2 perturbation, then combine compartment-resolved peptide tracing, quantitative MHC-I immunopeptidomics, T-cell activation, and rescue by catalytic-dead or endosome-targeting-defective LNPEP.
Hypothesis: LNPEP changes the presented peptide repertoire through a proteasome-dependent, cell-state-selective endosomal pathway whose TAP requirement depends on peptide source.
Type: human dendritic-cell epistasis and immunopeptidomics
Experiment: Create isoform-selective tags and splice edits in human trophoblast organoids, map cleavage by N-terminomics and protease screens, and compare membrane residence, shedding, oligomeric state, and oxytocin/vasopressin hydrolysis for each product at matched abundance.
Hypothesis: N-terminal splice variation and placental ectodomain cleavage independently regulate LNPEP trafficking and circulating peptide-hormone metabolism.
Type: isoform-resolved placental processing and enzymology
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The molecular mechanism by which the LNPEP cytosolic and transmembrane regions control GLUT4 sorting, and the degree to which this mechanism operates in human adipocytes in vivo, remain unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human adipocytes place LNPEP in insulin-responsive GLUT4 vesicles and show insulin-stimulated plasma-membrane recruitment. Mouse 3T3-L1 depletion and rescue experiments localize a GLUT4-retention function to the LNPEP cytosolic/transmembrane region rather than its catalytic ectodomain, but this noncatalytic mechanism has not been tested equivalently at the endogenous human locus.
Significance: Resolving this mechanism would separate LNPEP's established aminopeptidase activity from a potentially independent trafficking function relevant to insulin-responsive glucose transport.
What would resolve it: Introduce endogenous tail-motif and catalytic-site edits into primary human adipocytes or iPSC-derived adipocytes, then quantify GLUT4-vesicle composition, basal and insulin-stimulated exocytosis, glucose uptake, and rescue by matched membrane-tethered catalytic and noncatalytic constructs.
Provenance (the field's own admissions):
Gap: The peptide-import route, TAP contribution, substrate repertoire, and human dendritic-cell states that make LNPEP-dependent cross-presentation essential are not fully defined.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human dendritic-cell evidence establishes a proteasome-dependent pathway in which LNPEP trims exogenous peptide precursors in Rab14-positive endosomes, but it does not establish a universally TAP-independent mechanism. Mouse studies further show that the requirement differs between steady-state conventional and inflammatory dendritic-cell populations.
Significance: Defining the transport and cell-state logic is necessary to understand when LNPEP controls antigen repertoire and immune activation without conflating it with the distinct vacuolar pathway or cytosolic aminopeptidases.
What would resolve it: Combine acute LNPEP depletion with TAP1/2 perturbation, compartment-resolved immunopeptidomics, endosomal peptide-import assays, and rescue by catalytically inactive or localization-defective LNPEP in primary human dendritic-cell subsets under steady-state and inflammatory conditions.
Provenance (the field's own admissions):
Gap: Functional differences among the three annotated human LNPEP splice isoforms, and the protease and signals that generate the circulating pregnancy-serum ectodomain, remain poorly resolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: UniProt records two short N-terminal splice deletions and a proteolytically released chain beginning at residue 155, but current GO annotations do not demonstrate isoform-exclusive catalysis, trafficking, or antigen-processing functions. The serum product is cleavage-derived and must not be treated as a splice isoform.
Significance: Product-resolved evidence would clarify whether N-terminal variation alters targeting or regulation and how placental processing changes the enzyme's substrate access during pregnancy.
What would resolve it: Use isoform-selective endogenous tagging and splice editing in human placental, neuronal, and adipocyte models, coupled to N-terminomics of the shed product, protease perturbation, localization, trafficking, and matched substrate-cleavage assays.
Provenance (the field's own admissions):
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