| Structural highlights
Function
[AMPN_PIG] Broad specificity aminopeptidase. Plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. May be involved in the metabolism of regulatory peptides of diverse cell types, responsible for the processing of peptide hormones, such as angiotensin III and IV, neuropeptides, and chemokines and involved the cleavage of peptides bound to major histocompatibility complex class II molecules of antigen presenting cells. May have a role in angiogenesis (By similarity). It is able to degrade Leu-enkephalin and Met-enkephalin but not cholecystokinin CCK8, neuromedin C (GRP-10), somatostatin-14, substance P and vasoactive intestinal peptide. In case of porcine transmissible gastroenteritis coronavirus (TGEV) and porcine respiratory coronavirus (PRCoV) infections, serves as a receptor for TGEV and PRCoV spike glycoprotein in a species-specific manner.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Cell surface aminopeptidase N (APN) is a membrane-bound ectoenzyme that hydrolyzes proteins and peptides and regulates numerous cell functions. APN participates in tumor cell expansion and motility, and is a target for cancer therapies. Small drugs that bind to the APN active site inhibit catalysis and suppress tumor growth. APN is also a major cell entry receptor for coronavirus, which binds to a region distant from the active site. Three crystal structures that we determined of human and pig APN ectodomains defined the dynamic conformation of the protein. These structures offered snapshots of closed, intermediate and open APN, which represent distinct functional states. Coronavirus envelope proteins specifically recognized the open APN form, prevented ectodomain progression to the closed form and substrate hydrolysis. In addition, drugs that bind the active site inhibited both coronavirus binding to cell surface APN and infection; the drugs probably hindered APN transition to the virus-specific open form. We conclude that allosteric inhibition of APN functions occurs by ligand suppression of ectodomain motions necessary for catalysis and virus cell entry, as validated by locking APN with disulfides. Blocking APN dynamics can thus be a valuable approach to development of drugs that target this ectoenzyme.
Allosteric inhibition of aminopeptidase N functions related to tumor growth and virus infection.,Santiago C, Mudgal G, Reguera J, Recacha R, Albrecht S, Enjuanes L, Casasnovas JM Sci Rep. 2017 Apr 10;7:46045. doi: 10.1038/srep46045. PMID:28393915[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Delmas B, Gelfi J, Kut E, Sjostrom H, Noren O, Laude H. Determinants essential for the transmissible gastroenteritis virus-receptor interaction reside within a domain of aminopeptidase-N that is distinct from the enzymatic site. J Virol. 1994 Aug;68(8):5216-24. PMID:7913510
- ↑ Delmas B, Gelfi J, L'Haridon R, Vogel LK, Sjostrom H, Noren O, Laude H. Aminopeptidase N is a major receptor for the entero-pathogenic coronavirus TGEV. Nature. 1992 Jun 4;357(6377):417-20. PMID:1350661 doi:http://dx.doi.org/10.1038/357417a0
- ↑ Delmas B, Gelfi J, Sjostrom H, Noren O, Laude H. Further characterization of aminopeptidase-N as a receptor for coronaviruses. Adv Exp Med Biol. 1993;342:293-8. PMID:7911642
- ↑ Benbacer L, Kut E, Besnardeau L, Laude H, Delmas B. Interspecies aminopeptidase-N chimeras reveal species-specific receptor recognition by canine coronavirus, feline infectious peritonitis virus, and transmissible gastroenteritis virus. J Virol. 1997 Jan;71(1):734-7. PMID:8985407
- ↑ Hegyi A, Kolb AF. Characterization of determinants involved in the feline infectious peritonitis virus receptor function of feline aminopeptidase N. J Gen Virol. 1998 Jun;79 ( Pt 6):1387-91. PMID:9634079
- ↑ Santiago C, Mudgal G, Reguera J, Recacha R, Albrecht S, Enjuanes L, Casasnovas JM. Allosteric inhibition of aminopeptidase N functions related to tumor growth and virus infection. Sci Rep. 2017 Apr 10;7:46045. doi: 10.1038/srep46045. PMID:28393915 doi:http://dx.doi.org/10.1038/srep46045
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