Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Two new proteases in the MHC class I processing pathway.
-
The paper identifies puromycin-sensitive aminopeptidase and bleomycin hydrolase as cytosolic trimming enzymes, not LNPEP.
"By using specific selective criteria we purified two cytosolic proteolytic activities, puromycin-sensitive aminopeptidase and bleomycin hydrolase."
Oxytocin stimulates the translocation of oxytocinase of human vascular endothelial cells via activation of oxytocin receptors.
-
Oxytocin drives LNPEP/oxytocinase translocation to the surface of human umbilical vascular endothelial cells through an oxytocin-receptor and PKC-dependent pathway.
"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."
Identification of a tankyrase-binding motif shared by IRAP, TAB182, and human TRF1 but not mouse TRF1. NuMA contains this RXXPDG motif and is a novel tankyrase partner.
-
LNPEP/IRAP binds tankyrases through a shared RXXPDG recognition motif.
"Herein we describe a novel RXXPDG motif shared by IRAP, TAB182, and human TRF1 that mediates their binding to tankyrases."
Regulation of the human leukocyte-derived arginine aminopeptidase/endoplasmic reticulum-aminopeptidase 2 gene by interferon-gamma.
-
The study concerns the ERAP2/L-RAP gene and explicitly distinguishes it from placental leucine aminopeptidase.
"The entire genomic structure of the L-RAP gene is similar to both placental leucine aminopeptidase (P-LAP) and adipocyte-derived leucine aminopeptidase (A-LAP) genes, confirming the close relationship of these three enzymes."
Integral and associated lysosomal membrane proteins.
-
The study catalogued proteins enriched in purified placental lysosomal membranes.
"In membranes purified from placental lysosomes, we identified 58 proteins, known to reside at least partially in the lysosomal membrane."
IRAP identifies an endosomal compartment required for MHC class I cross-presentation.
-
Human dendritic-cell IRAP localizes to a Rab14-positive endosomal compartment, associates with MHC-I molecules, and is required for cross-presentation.
"In human dendritic cells, IRAP was localized to a Rab14+ endosomal storage compartment in which it interacted with MHC class I molecules."
-
The demonstrated IRAP route performs final peptide trimming in proteasome-dependent cross-presentation.
"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."
Different cross-presentation pathways in steady-state and inflammatory dendritic cells.
-
IRAP-dependent cross-presentation is required in inflammatory monocyte-derived dendritic cells but dispensable in steady-state CD8-positive dendritic cells.
"We demonstrate that IRAP and MR are dispensable for cross-presentation by CD8 + DC and for cross-priming."
-
The paper confirms an IRAP-dependent pathway in inflammatory dendritic cells.
"However, cross-presentation was impaired in moDC deficient in IRAP or MR, confirming the role of these two molecules in inflammatory DC."
Defining the membrane proteome of NK cells.
-
The study used stringent membrane isolation and proteomics in the YTS natural-killer-like cell line.
"The present study was initiated to define the composition of the membrane proteome of the Natural Killer (NK) like cell line YTS."
Structural basis and sequence rules for substrate recognition by Tankyrase explain the basis for cherubism disease.
-
Tankyrase ankyrin-repeat clusters recognize a defined peptide consensus shared across validated targets.
"Using a solution-based peptide library screen, we derive a rule-based consensus for Tankyrase substrates common to four functionally conserved ARCs."
A proteome-scale map of the human interactome network.
-
HI-II-14 is a systematic human binary protein-interaction map rather than focused LNPEP mechanistic work.
"Here, we describe a systematic map of ?14,000 high-quality human binary protein-protein interactions."
IRAP deficiency attenuates diet-induced obesity in mice through increased energy expenditure.
-
Mouse IRAP deficiency increases energy expenditure and UCP1-associated thermogenic features during diet-induced obesity.
"Analysis of brown adipose tissue (BAT) in IRAP(-/-) showed increased levels of uncoupling protein-1 (UCP-1) at basal level and adaptive thermogenesis was not impaired."
A reference map of the human binary protein interactome.
-
HuRI systematically maps binary human interactions, but most individual edges lack a known cellular function.
"While HuRI displays highly significant overlap with known functional relationships, the cellular function of most individual PPIs remains to be elucidated."
-
The experiment tested one construct per gene, limiting isoform-specific conclusions.
"Screening only one isoform per gene also misses interaction partners specific to alternative spliceforms50."
Human placental leucine aminopeptidase/oxytocinase. A new member of type II membrane-spanning zinc metallopeptidase family.
-
Human P-LAP/LNPEP is a type-II integral membrane zinc metallopeptidase that degrades oxytocin and vasopressin and can be released into blood.
"These results suggest that the enzyme is synthesized as an integral membrane protein and is released into blood under some physiological conditions."
-
The human sequence contains the defining HEXXH zinc-metallopeptidase motif.
"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."
The complete amino acid sequence of human placental oxytocinase.
-
Human oxytocinase is a 1025-residue type-II membrane gluzincin with 110 cytosolic residues, a transmembrane segment, and an extracellular catalytic region.
"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."
Interferon-gamma can stimulate post-proteasomal trimming of the N terminus of an antigenic peptide by inducing leucine aminopeptidase.
-
The experiment identifies an interferon-induced soluble cytosolic LAP activity, not LNPEP/IRAP.
"One was induced by IFN-gamma and was identified immunologically as leucine aminopeptidase (LAP)."
Expression of placental leucine aminopeptidase/oxytocinase in neuronal cells and its action on neuronal peptides.
-
Human LNPEP is membrane associated in brain/neuronal cells and degrades Met-enkephalin and dynorphin.
"P-LAP was shown to degrade several bioactive neuropeptides such as Met-enkephalin and dynorphin A (1-8)."
-
Unlike placenta, brain and PC12 cells showed no soluble LNPEP form.
"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."
Evidence that the angiotensin IV (AT(4)) receptor is the enzyme insulin-regulated aminopeptidase.
-
Purification, peptide sequencing, and transfected-cell binding identify IRAP as the high-affinity angiotensin IV binding site.
"Here we identify the AT(4) receptor, by protein purification and peptide sequencing, to be insulin-regulated aminopeptidase (IRAP)."
-
Angiotensin IV-family ligands inhibit LNPEP catalytic activity.
"We also show that AT(4) receptor ligands dose-dependently inhibit the catalytic activity of IRAP."
Adipocytes exhibit abnormal subcellular distribution and translocation of vesicles containing glucose transporter 4 and insulin-regulated aminopeptidase in type 2 diabetes mellitus: implications regarding defects in vesicle trafficking.
-
Human adipocytes contain LNPEP/IRAP in GLUT4-associated membrane vesicles and recruit it to the plasma membrane in response to insulin.
"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."
Insulin-stimulated exocytosis of GLUT4 is enhanced by IRAP and its partner tankyrase.
-
In 3T3-L1 adipocytes, IRAP depletion impairs insulin-stimulated GLUT4 translocation and tankyrase depletion impairs GSV movement and glucose uptake.
"By contrast, insulin-stimulated GLUT4 translocation was impaired upon IRAP knockdown, indicating that IRAP plays a role in GSV trafficking."
Identification of human placental leucine aminopeptidase as oxytocinase.
-
Purified human placental LNPEP hydrolyzes oxytocin, vasopressin, and angiotensin III.
"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."
Insulin-regulated aminopeptidase is a key regulator of GLUT4 trafficking by controlling the sorting of GLUT4 from endosomes to specialized insulin-regulated vesicles.
-
IRAP depletion in 3T3-L1 adipocytes accelerates basal GLUT4 exocytosis and redistributes GLUT4 from specialized storage vesicles to endosomes.
"IRAP-knockdown (KD) resulted in a two- to threefold increase in basal PM GLUT4, due to accelerated exocytosis that correlated with a partial redistribution of GLUT4 to rapidly recycling endosomes."
-
Rescue by full-length IRAP or an IRAP-transferrin-receptor chimera localizes the retention function to the cytosolic/transmembrane region rather than catalytic activity.
"This increased exocytosis was rescued by reexpression of either full-length IRAP or IRAP-TR (Figure 3A)."
UniProt entry Q9UIQ6 (LCAP_HUMAN), leucyl-cystinyl aminopeptidase
-
Reviewed UniProt defines LNPEP as a single-pass type-II membrane M1 aminopeptidase with a cytosolic N terminus and extracellular/luminal catalytic domain; a proteolytically released pregnancy-serum product is also recorded.
"CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:11389728};"
Trimming of peptides by IRAP in endocytic vesicles
-
Reactome places IRAP-mediated peptide trimming in early/recycling endosomes and describes a proteasome-dependent cytosol-to-endosome route.
"IRAP is detected predominantly in the early and recycling endosome fractions."
Endosomal/Vacuolar pathway
-
This Reactome pathway describes a proteasome- and TAP-independent vacuolar route for exogenous-antigen presentation.
"Some antigens are cross-presented through a vacuolar mechanism that involves generation of antigenic peptides and their loading on to MHC-I molecules within the endosomal compartment in a proteasome and TAP-independent manner."
Trimming of N-ter extended precursor fragments by cytosolic aminopeptidases
-
Reactome lists TPP2, PSA, bleomycin hydrolase, and LAP as soluble cytosolic trimming enzymes.
"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)."
Antigen processing: Ubiquitination & Proteasome degradation
-
The pathway describes E1/E2/E3-mediated polyubiquitination and proteasomal generation of MHC-I peptide precursors.
"This process involves three classes of enzyme, an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase."