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NLN (gene)

From Wikipedia, the free encyclopedia

NLN
Identifiers
AliasesNLN, AGTBP, EP24.16, MEP, MOP, neurolysin
External IDsOMIM: 611530; MGI: 1923055; HomoloGene: 69315; GeneCards: NLN; OMA:NLN - orthologs
Orthologs
SpeciesHumanMouse
Entrez

57486

75805

Ensembl

ENSG00000123213

ENSMUSG00000021710

UniProt

Q9BYT8

Q91YP2

RefSeq (mRNA)

NM_020726

NM_029447

RefSeq (protein)

NP_065777

NP_083723

Location (UCSC)Chr 5: 65.72 – 65.87 MbChr 13: 104.16 – 104.25 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Neurolysin, mitochondrial is a protein that in humans is encoded by the NLN gene.[5][6] It is a 78-kDa enzyme, widely distributed in mammalian tissues and found in various subcellular locations that vary with cell type.[7] Neurolysin exemplifies the ability of neuropeptidases to target various cleavage site sequences by hydrolyzing them in vitro,[8][9] and metabolism of neurotensin is the most important role of neurolysin in vivo.[10] Neurolysin has also been implicated in pain control,[11][12][13] blood pressure regulation,[14][15] sepsis,[16] reproduction,[17][18] cancer biology[19] pathogenesis of stroke,[20] and glucose metabolism.[21]

Structure

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Gene

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The NLN gene lies on the chromosome location of 5q12.3 and consists of 14 exons.

Protein

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Neurolysin, with 704 amino acid residues, is a zinc metalloendopeptidase with a conserved HEXXH motif. It has an overall prolate ellipsoid shape, with a deep narrow channel dividing it into two roughly equal domains.[22] The catalytic site is contained within a thermolysin-like region found in many metallopeptidases and located in the domain near the floor of the channel.[10][23]

Function

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Neurolysin hydrolyzes only peptides containing 5-17 amino acids by cleaving at a limited set of sites.[22][24][25] The specificity of neurolysin for small bioactive peptides is due to the presence of large structural elements erected over its active site region that allow substrates access only through a deep narrow channel.[26] In vitro, neurolysin exemplifies the ability of some neuropeptidases to target diverse cleavage site sequences.[8][9] In vivo, their most established role is cleaving neurotensin between its 10th and 11th residues to produce inactive fragments and it has been recently identified as a non-AT1-non-AT2 angiotensin-binding site, with function pertaining to the rennin-angiotensin system.[10][27][28] Neurotensin is involved in many processes including mast cell degranulation and regulation of central nervous system dopaminergic and cholinergic circuits.[29][30][31] A lower level of neurotensin is associated with schizophrenia,[32] and it is implicated in cardiovascular disorders, addiction, Huntington disease and Parkinson disease.[30][33][34][35] Neurotensin is also one of the most potent blockers of pain perception.[36]

Clinical significance

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Metabolism of neurotensin is the most important role of neurolysin in vivo and has been identified as a non-AT1-non-AT2 angiotensin-binding site.[10][27][28] Neurotensin is involved in many processes including mast cell degranullation and regulation of central nervous system dopaminergic and cholinergic circuits.[29][30][31] Neurolysin has also been implicated in pain control,[11][12][13] blood pressure regulation,[14][15] sepsis,[16] reproduction,[17][18] cancer biology,[19] pathogenesis of stroke,[20] and glucose metabolism.[21] Inhibition of neurolysin has been shown to produce neurotensin-induced analgesia in mice,[37] and control of neurotensin levels by neurolysin may serve as a potential target for antipsychotic therapies.

Interactions

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This protein is known to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000123213 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021710 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Nagase T, Ishikawa K, Kikuno R, Hirosawa M, Nomura N, Ohara O (October 1999). "Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro". DNA Research. 6 (5): 337–45. doi:10.1093/dnares/6.5.337. PMID 10574462.
  6. ^ "Entrez Gene: NLN neurolysin (metallopeptidase M3 family)".
  7. ^ Barrett AJ, Brown MA, Dando PM, Knight CG, McKie N, Rawlings ND, Serizawa A (1995). "Thimet oligopeptidase and oligopeptidase M or neurolysin". Proteolytic Enzymes: Aspartic and Metallo Peptidases. Methods in Enzymology. Vol. 248. pp. 529–56. doi:10.1016/0076-6879(95)48034-x. ISBN 9780121821494. PMID 7674943.
  8. ^ a b Oliveira V, Campos M, Hemerly JP, Ferro ES, Camargo AC, Juliano MA, Juliano L (May 2001). "Selective neurotensin-derived internally quenched fluorogenic substrates for neurolysin (EC 3.4.24.16): comparison with thimet oligopeptidase (EC 3.4.24.15) and neprilysin (EC 3.4.24.11)". Analytical Biochemistry. 292 (2): 257–65. doi:10.1006/abio.2001.5083. PMID 11355859.
  9. ^ a b Rioli V, Kato A, Portaro FC, Cury GK, te Kaat K, Vincent B, Checler F, Camargo AC, Glucksman MJ, Roberts JL, Hirose S, Ferro ES (September 1998). "Neuropeptide specificity and inhibition of recombinant isoforms of the endopeptidase 3.4.24.16 family: comparison with the related recombinant endopeptidase 3.4.24.15". Biochemical and Biophysical Research Communications. 250 (1): 5–11. doi:10.1006/bbrc.1998.8941. PMID 9735321.
  10. ^ a b c d e Hines CS, Ray K, Schmidt JJ, Xiong F, Feenstra RW, Pras-Raves M, de Moes JP, Lange JH, Melikishvili M, Fried MG, Mortenson P, Charlton M, Patel Y, Courtney SM, Kruse CG, Rodgers DW (December 2014). "Allosteric inhibition of the neuropeptidase neurolysin". The Journal of Biological Chemistry. 289 (51): 35605–19. doi:10.1074/jbc.M114.620930. PMC 4271243. PMID 25378390.
  11. ^ a b Jeske NA, Berg KA, Cousins JC, Ferro ES, Clarke WP, Glucksman MJ, Roberts JL (April 2006). "Modulation of bradykinin signaling by EP24.15 and EP24.16 in cultured trigeminal ganglia". Journal of Neurochemistry. 97 (1): 13–21. doi:10.1111/j.1471-4159.2006.03706.x. PMID 16515556. S2CID 24664221.
  12. ^ a b Doulut S, Dubuc I, Rodriguez M, Vecchini F, Fulcrand H, Barelli H, Checler F, Bourdel E, Aumelas A, Lallement JC (May 1993). "Synthesis and analgesic effects of N-[3-[(hydroxyamino) carbonyl]-1-oxo-2(R)-benzylpropyl]-L-isoleucyl-L-leucine, a new potent inhibitor of multiple neurotensin/neuromedin N degrading enzymes". Journal of Medicinal Chemistry. 36 (10): 1369–79. doi:10.1021/jm00062a009. PMID 8496905.
  13. ^ a b Barelli H, Fox-Threlkeld JE, Dive V, Daniel EE, Vincent JP, Checler F (May 1994). "Role of endopeptidase 3.4.24.16 in the catabolism of neurotensin, in vivo, in the vascularly perfused dog ileum". British Journal of Pharmacology. 112 (1): 127–32. doi:10.1111/j.1476-5381.1994.tb13041.x. PMC 1910296. PMID 8032633.
  14. ^ a b Oliveira EB, Souza LL, Sivieri DO, Bispo-da-Silva LB, Pereira HJ, Costa-Neto CM, Sousa MV, Salgado MC (December 2007). "Carboxypeptidase B and other kininases of the rat coronary and mesenteric arterial bed perfusates". American Journal of Physiology. Heart and Circulatory Physiology. 293 (6): H3550-7. doi:10.1152/ajpheart.00784.2007. PMID 17906107. S2CID 23115730.
  15. ^ a b Blais PA, Côté J, Morin J, Larouche A, Gendron G, Fortier A, Regoli D, Neugebauer W, Gobeil F (August 2005). "Hypotensive effects of hemopressin and bradykinin in rabbits, rats and mice. A comparative study". Peptides. 26 (8): 1317–22. doi:10.1016/j.peptides.2005.03.026. PMID 16042973. S2CID 36463460.
  16. ^ a b c Piliponsky AM, Chen CC, Nishimura T, Metz M, Rios EJ, Dobner PR, Wada E, Wada K, Zacharias S, Mohanasundaram UM, Faix JD, Abrink M, Pejler G, Pearl RG, Tsai M, Galli SJ (April 2008). "Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis". Nature Medicine. 14 (4): 392–8. doi:10.1038/nm1738. PMC 2873870. PMID 18376408.
  17. ^ a b Dauch P, Masuo Y, Vincent JP, Checler F (November 1992). "Endopeptidase 24-16 in murines: tissue distribution, cerebral regionalization, and ontogeny". Journal of Neurochemistry. 59 (5): 1862–7. doi:10.1111/j.1471-4159.1992.tb11021.x. PMID 1402928. S2CID 41539518.
  18. ^ a b Shrimpton CN, Smith AI, Lew RA (October 2002). "Soluble metalloendopeptidases and neuroendocrine signaling". Endocrine Reviews. 23 (5): 647–64. doi:10.1210/er.2001-0032. PMID 12372844.
  19. ^ a b Paschoalin T, Carmona AK, Rodrigues EG, Oliveira V, Monteiro HP, Juliano MA, Juliano L, Travassos LR (9 July 2007). "Characterization of thimet oligopeptidase and neurolysin activities in B16F10-Nex2 tumor cells and their involvement in angiogenesis and tumor growth". Molecular Cancer. 6: 44. doi:10.1186/1476-4598-6-44. PMC 1965469. PMID 17620116.
  20. ^ a b Rashid M, Wangler NJ, Yang L, Shah K, Arumugam TV, Abbruscato TJ, Karamyan VT (April 2014). "Functional up-regulation of endopeptidase neurolysin during post-acute and early recovery phases of experimental stroke in mouse brain". Journal of Neurochemistry. 129 (1): 179–89. doi:10.1111/jnc.12513. PMID 24164478. S2CID 206089871.
  21. ^ a b Cavalcanti DM, Castro LM, Rosa Neto JC, Seelaender M, Neves RX, Oliveira V, Forti FL, Iwai LK, Gozzo FC, Todiras M, Schadock I, Barros CC, Bader M, Ferro ES (May 2014). "Neurolysin knockout mice generation and initial phenotype characterization". The Journal of Biological Chemistry. 289 (22): 15426–40. doi:10.1074/jbc.M113.539148. PMC 4140899. PMID 24719317.
  22. ^ a b Brown CK, Madauss K, Lian W, Beck MR, Tolbert WD, Rodgers DW (March 2001). "Structure of neurolysin reveals a deep channel that limits substrate access". Proceedings of the National Academy of Sciences of the United States of America. 98 (6): 3127–32. Bibcode:2001PNAS...98.3127B. doi:10.1073/pnas.051633198. PMC 30618. PMID 11248043.
  23. ^ Matthews BW, Weaver LH, Kester WR (December 1974). "The conformation of thermolysin". The Journal of Biological Chemistry. 249 (24): 8030–44. doi:10.1016/S0021-9258(19)42067-X. PMID 4214815.
  24. ^ Ray K, Hines CS, Rodgers DW (September 2002). "Mapping sequence differences between thimet oligopeptidase and neurolysin implicates key residues in substrate recognition". Protein Science. 11 (9): 2237–46. doi:10.1110/ps.0216302. PMC 2373592. PMID 12192079.
  25. ^ Yanagihara N, Toyohira Y, Yamamoto H, Ohta Y, Tsutsui M, Miyamoto E, Izumi F (September 1994). "Occurrence and activation of Ca2+/calmodulin-dependent protein kinase II and its endogenous substrates in bovine adrenal medullary cells". Molecular Pharmacology. 46 (3): 423–30. PMID 7935321.
  26. ^ Rioli V, Gozzo FC, Heimann AS, Linardi A, Krieger JE, Shida CS, Almeida PC, Hyslop S, Eberlin MN, Ferro ES (March 2003). "Novel natural peptide substrates for endopeptidase 24.15, neurolysin, and angiotensin-converting enzyme". The Journal of Biological Chemistry. 278 (10): 8547–55. doi:10.1074/jbc.M212030200. PMID 12500972.
  27. ^ a b Swindle JD, Santos KL, Speth RC (October 2013). "Pharmacological characterization of a novel non-AT1, non-AT2 angiotensin binding site identified as neurolysin". Endocrine. 44 (2): 525–31. doi:10.1007/s12020-013-9898-x. PMC 3742649. PMID 23412923.
  28. ^ a b Wangler NJ, Santos KL, Schadock I, Hagen FK, Escher E, Bader M, Speth RC, Karamyan VT (January 2012). "Identification of membrane-bound variant of metalloendopeptidase neurolysin (EC 3.4.24.16) as the non-angiotensin type 1 (non-AT1), non-AT2 angiotensin binding site". The Journal of Biological Chemistry. 287 (1): 114–22. doi:10.1074/jbc.M111.273052. PMC 3249063. PMID 22039052.
  29. ^ a b Alexacos N, Pang X, Boucher W, Cochrane DE, Sant GR, Theoharides TC (May 1999). "Neurotensin mediates rat bladder mast cell degranulation triggered by acute psychological stress". Urology. 53 (5): 1035–40. doi:10.1016/s0090-4295(98)00627-x. PMID 10223502.
  30. ^ a b c Rostène W, Brouard A, Dana C, Masuo Y, Agid F, Vial M, Lhiaubet AM, Pelaprat D (1992). "Interaction between neurotensin and dopamine in the brain. Morphofunctional and clinical evidence". Annals of the New York Academy of Sciences. 668: 217–31. doi:10.1111/j.1749-6632.1992.tb27352.x. PMID 1361114. S2CID 41673524.
  31. ^ a b Margeta-Mitrovic M, Grigg JJ, Koyano K, Nakajima Y, Nakajima S (September 1997). "Neurotensin and substance P inhibit low- and high-voltage-activated Ca2+ channels in cultured newborn rat nucleus basalis neurons". Journal of Neurophysiology. 78 (3): 1341–52. doi:10.1152/jn.1997.78.3.1341. PMID 9310425.
  32. ^ Sharma RP, Janicak PG, Bissette G, Nemeroff CB (July 1997). "CSF neurotensin concentrations and antipsychotic treatment in schizophrenia and schizoaffective disorder". The American Journal of Psychiatry. 154 (7): 1019–21. doi:10.1176/ajp.154.7.1019. PMID 9210757.
  33. ^ Ertl G, Bauer B, Becker HH, Rose G (April 1993). "Effects of neurotensin and neuropeptide Y on coronary circulation and myocardial function in dogs". The American Journal of Physiology. 264 (4 Pt 2): H1062-8. doi:10.1152/ajpheart.1993.264.4.H1062. PMID 8476083.
  34. ^ Pang X, Alexacos N, Letourneau R, Seretakis D, Gao W, Boucher W, Cochrane DE, Theoharides TC (October 1998). "A neurotensin receptor antagonist inhibits acute immobilization stress-induced cardiac mast cell degranulation, a corticotropin-releasing hormone-dependent process". The Journal of Pharmacology and Experimental Therapeutics. 287 (1): 307–14. PMID 9765351.
  35. ^ Fredrickson P, Boules M, Lin SC, Richelson E (September 2005). "Neurobiologic basis of nicotine addiction and psychostimulant abuse: a role for neurotensin?". The Psychiatric Clinics of North America. 28 (3): 737–51, 746. doi:10.1016/j.psc.2005.05.001. PMID 16122577.
  36. ^ Luttinger D, Nemeroff CB, Prange AJ (April 1982). "The effects of neuropeptides on discrete-trial conditioned avoidance responding". Brain Research. 237 (1): 183–92. doi:10.1016/0006-8993(82)90566-2. PMID 6176291. S2CID 20135629.
  37. ^ Vincent B, Jiracek J, Noble F, Loog M, Roques B, Dive V, Vincent JP, Checler F (June 1997). "Effect of a novel selective and potent phosphinic peptide inhibitor of endopeptidase 3.4.24.16 on neurotensin-induced analgesia and neuronal inactivation". British Journal of Pharmacology. 121 (4): 705–10. doi:10.1038/sj.bjp.0701182. PMC 1564740. PMID 9208137.
  38. ^ Denner J, Eschricht M, Lauck M, Semaan M, Schlaermann P, Ryu H, Akyüz L (2013). "Modulation of cytokine release and gene expression by the immunosuppressive domain of gp41 of HIV-1". PLOS ONE. 8 (1): e55199. Bibcode:2013PLoSO...855199D. doi:10.1371/journal.pone.0055199. PMC 3559347. PMID 23383108.

Further reading

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