Alternative titles; symbols
HGNC Approved Gene Symbol: LNPEP
Cytogenetic location: 5q15 Genomic coordinates (GRCh38): 5:96,936,080-97,037,513 (from NCBI)
Beckman et al. (1966) found 3 placental leucine aminopeptidase (LAP) types. (LAP enzymes in the serum of pregnant women probably are not derived from placenta.) Beckman et al. (1969) stated a preference for the designation amino acid naphthylamidase. The serum level of placental LAP increases during pregnancy and degrades several peptide hormones such as oxytocin (167050) and vasopressin (192340).
Rogi et al. (1996) cloned a human placenta cDNA encoding leucyl-cystinyl aminopeptidase, which they symbolized PLAP. The deduced 944-amino acid polypeptide contains the HEXXH consensus sequence of zinc metallopeptidases as well as an N-terminal hydrophobic region that resembles a transmembrane domain. Northern blot analysis detected expression of 3.6-kb and 10.5-kb transcripts in placenta, heart, and skeletal muscle, and a 10.5-kb transcript in brain. Using immunohistochemistry, Nagasaka et al. (1997) localized LNPEP to syncytiotrophoblasts in placenta as well as in fetal and adult vascular endothelial cells, the epithelial lining of several organs, neurons, and sweat gland cells; adult seminal vesicles and prostate; and fetal adipocytes and skeletal muscle.
In muscle and fat cells, insulin (INS; 176730) stimulation activates a signaling cascade that causes intracellular vesicles containing glucose transporter-4 (GLUT4, or SLC2A4; 138190) to translocate to and fuse with the plasma membrane. Using mass spectrometry, Larance et al. (2005) identified Irap as a major membrane protein associated with Glut4 vesicles in cultured mouse adipocytes. The Rab GTPase-activating protein As160 (TBC1D4; 612465), another major constituent of Glut4 vesicles, interacted directly with the cytoplasmic tail of Irap in vitro and in vivo. Since As160 dissociated from Glut4 vesicles upon insulin stimulation, Larance et al. (2005) concluded that interaction between AS160 and IRAP mediates association of AS160 with GLUT4 vesicles.
Major histocompatibility complex (MHC) class I molecules present peptides, produced through cytosolic proteasomal degradation of cellular proteins, to cytotoxic T lymphocytes. In dendritic cells, the peptides can also be derived from internalized antigens through a process known as crosspresentation. Saveanu et al. (2009) identified a role for peptide trimming by IRAP in crosspresentation. In human dendritic cells, IRAP was localized to a Rab14+ endosomal storage compartment in which it interacted with MHC class I molecules. IRAP deficiency compromised crosspresentation in vitro and in vivo but did not affect endogenous presentation. Saveanu et al. (2009) proposed the existence of 2 pathways for proteasome-dependent crosspresentation in which final peptide trimming involves IRAP in endosomes and involves the related aminopeptidases in the endoplasmic reticulum.
Horio et al. (1999) isolated and sequenced genomic clones containing the upstream region of LNPEP and identified 4 GC-rich sequences, a TATA box, and 3 half palindromic estrogen-responsive element (ERE)-like motifs.
By FISH, Horio et al. (1999) mapped the LNPEP gene to chromosome 5q14.2-q15.
Mouse Irap, a zinc-dependent membrane aminopeptidase, is the homolog of human LNPEP. Keller et al. (2002) characterized Irap-null mice with regard to glucose homeostasis and regulation of the insulin-responsive glucose transporter Glut4 (138190). Irap-null mice maintained normal glucose homeostasis despite decreased glucose uptake into muscle and fat cells. The absence of Irap did not affect the subcellular distribution of Glut4 in adipocytes, but it led to a substantial decrease in Glut4 expression.
Beckman, L., Beckman, G., Mi, M. P., De Simone, J. The human placental amino acid naphthylamidases: their molecular interrelations and correlations with perinatal factors. Hum. Hered. 19: 249-257, 1969. [PubMed: 5361488] [Full Text: https://doi.org/10.1159/000152226]
Beckman, L., Bjorling, G., Christodoulou, C. Pregnancy enzymes and placental polymorphism. II. Leucine aminopeptidase. Acta Genet. Statist. Med. 16: 122-131, 1966. [PubMed: 5953194] [Full Text: https://doi.org/10.1159/000151957]
Horio, J., Nomura, S., Okada, M., Katsumata, Y., Nakanishi, Y., Kumano, Y., Takami, S., Kinoshita, M., Tsujimoto, M., Nakazato, H., Mizutani, S. Structural organization of the 5-prime-end and chromosomal assignment of human placental leucine aminopeptidase/insulin-regulated membrane aminopeptidase gene. Biochem. Biophys. Res. Commun. 262: 269-274, 1999. [PubMed: 10448104] [Full Text: https://doi.org/10.1006/bbrc.1999.1184]
Keller, S. R., Davis, A. C., Clairmont, K. B. Mice deficient in the insulin-regulated membrane aminopeptidase show substantial decreases in glucose transporter GLUT4 levels but maintain normal glucose homeostasis. J. Biol. Chem. 277: 17677-17686, 2002. [PubMed: 11884418] [Full Text: https://doi.org/10.1074/jbc.M202037200]
Larance, M., Ramm, G., Stockli, J., van Dam, E. M., Winata, S., Wasinger, V., Simpson, F., Graham, M., Junutula, J. R., Guilhaus, M., James, D. E. Characterization of the role of the Rab GTPase-activating protein AS160 in insulin-regulated GLUT4 trafficking. J. Biol. Chem. 280: 37803-37813, 2005. [PubMed: 16154996] [Full Text: https://doi.org/10.1074/jbc.M503897200]
Nagasaka, T., Nomura, S., Okamura, M., Tsujimoto, M., Nakazato, H., Oiso, Y., Nakashima, N., Mizutani, S. Immunohistochemical localization of placental leucine aminopeptidase/oxytocinase in normal human placental, fetal and adult tissues. Reprod. Fertil. Dev. 9: 747-753, 1997. [PubMed: 9733056] [Full Text: https://doi.org/10.1071/r97055]
Rogi, T., Tsujimoto, M., Nakazato, H., Mizutani, S., Tomoda, Y. Human placental leucine aminopeptidase/oxytocinase: a new member of type II membrane-spanning zinc metallopeptidase family. J. Biol. Chem. 271: 56-61, 1996. [PubMed: 8550619] [Full Text: https://doi.org/10.1074/jbc.271.1.56]
Saveanu, L., Carroll, O., Weimershaus, M., Guermonprez, P., Firat, E., Lindo, V., Greer, F., Davoust, J., Kratzer, R., Keller, S. R., Niedermann, G., van Endert, P. IRAP identifies an endosomal compartment required for MHC class I cross-presentation. Science 325: 213-217, 2009. [PubMed: 19498108] [Full Text: https://doi.org/10.1126/science.1172845]
Scandalios, J. G. Human serum leucine aminopeptidase: variation in pregnancy and in disease states. J. Hered. 58: 153-156, 1967. [PubMed: 5234063] [Full Text: https://doi.org/10.1093/oxfordjournals.jhered.a107571]