Biology:NLN (gene)

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Neurolysin, mitochondrial is a protein that in humans is encoded by the NLN gene.[1][2] It is a 78-kDa enzyme, widely distributed in mammalian tissues and found in various subcellular locations that vary with cell type.[3] Neurolysin exemplifies the ability of neuropeptidases to target various cleavage site sequences by hydrolyzing them in vitro,[4][5] and metabolism of neurotensin is the most important role of neurolysin in vivo.[6] Neurolysin has also been implicated in pain control,[7][8][9] blood pressure regulation,[10][11] sepsis,[12] reproduction,[13][14] cancer biology[15] pathogenesis of stroke,[16] and glucose metabolism.[17]

Structure

Gene

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

Protein

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.[18] 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.[6][19]

Function

Neurolysin hydrolyzes only peptides containing 5-17 amino acids by cleaving at a limited set of sites.[18][20][21] 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.[22] In vitro, neurolysin exemplifies the ability of some neuropeptidases to target diverse cleavage site sequences.[4][5] 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.[6][23][24] Neurotensin is involved in many processes including mast cell degranulation and regulation of central nervous system dopaminergic and cholinergic circuits.[25][26][27] A lower level of neurotensin is associated with schizophrenia,[28] and it is implicated in cardiovascular disorders, addiction, Huntington disease and Parkinson disease.[26][29][30][31] Neurotensin is also one of the most potent blockers of pain perception.[32]

Clinical significance

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.[6][23][24] Neurotensin is involved in many processes including mast cell degranullation and regulation of central nervous system dopaminergic and cholinergic circuits.[25][26][27] Neurolysin has also been implicated in pain control,[7][8][9] blood pressure regulation,[10][11] sepsis,[12] reproduction,[13][14] cancer biology,[15] pathogenesis of stroke,[16] and glucose metabolism.[17] Inhibition of neurolysin has been shown to produce neurotensin-induced analgesia in mice,[33] and control of neurotensin levels by neurolysin may serve as a potential target for antipsychotic therapies.

Interactions

This protein is known to interact with:

References

  1. ↑ "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. October 1999. doi:10.1093/dnares/6.5.337. PMID 10574462. 
  2. ↑ "Entrez Gene: NLN neurolysin (metallopeptidase M3 family)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=57486. 
  3. ↑ "Thimet oligopeptidase and oligopeptidase M or neurolysin". Methods in Enzymology 248: 529–56. 1995. doi:10.1016/0076-6879(95)48034-x. PMID 7674943. 
  4. ↑ 4.0 4.1 "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. May 2001. doi:10.1006/abio.2001.5083. PMID 11355859. 
  5. ↑ 5.0 5.1 "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. September 1998. doi:10.1006/bbrc.1998.8941. PMID 9735321. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Allosteric inhibition of the neuropeptidase neurolysin". The Journal of Biological Chemistry 289 (51): 35605–19. December 2014. doi:10.1074/jbc.M114.620930. PMID 25378390. 
  7. ↑ 7.0 7.1 "Modulation of bradykinin signaling by EP24.15 and EP24.16 in cultured trigeminal ganglia". Journal of Neurochemistry 97 (1): 13–21. April 2006. doi:10.1111/j.1471-4159.2006.03706.x. PMID 16515556. 
  8. ↑ 8.0 8.1 "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. May 1993. doi:10.1021/jm00062a009. PMID 8496905. 
  9. ↑ 9.0 9.1 "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. May 1994. doi:10.1111/j.1476-5381.1994.tb13041.x. PMID 8032633. 
  10. ↑ 10.0 10.1 "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. December 2007. doi:10.1152/ajpheart.00784.2007. PMID 17906107. 
  11. ↑ 11.0 11.1 "Hypotensive effects of hemopressin and bradykinin in rabbits, rats and mice. A comparative study". Peptides 26 (8): 1317–22. August 2005. doi:10.1016/j.peptides.2005.03.026. PMID 16042973. 
  12. ↑ 12.0 12.1 12.2 "Neurotensin increases mortality and mast cells reduce neurotensin levels in a mouse model of sepsis". Nature Medicine 14 (4): 392–8. April 2008. doi:10.1038/nm1738. PMID 18376408. 
  13. ↑ 13.0 13.1 "Endopeptidase 24-16 in murines: tissue distribution, cerebral regionalization, and ontogeny". Journal of Neurochemistry 59 (5): 1862–7. November 1992. doi:10.1111/j.1471-4159.1992.tb11021.x. PMID 1402928. 
  14. ↑ 14.0 14.1 "Soluble metalloendopeptidases and neuroendocrine signaling". Endocrine Reviews 23 (5): 647–64. October 2002. doi:10.1210/er.2001-0032. PMID 12372844. 
  15. ↑ 15.0 15.1 "Characterization of thimet oligopeptidase and neurolysin activities in B16F10-Nex2 tumor cells and their involvement in angiogenesis and tumor growth". Molecular Cancer 6: 44. 9 July 2007. doi:10.1186/1476-4598-6-44. PMID 17620116. 
  16. ↑ 16.0 16.1 "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. April 2014. doi:10.1111/jnc.12513. PMID 24164478. 
  17. ↑ 17.0 17.1 "Neurolysin knockout mice generation and initial phenotype characterization". The Journal of Biological Chemistry 289 (22): 15426–40. May 2014. doi:10.1074/jbc.M113.539148. PMID 24719317. 
  18. ↑ 18.0 18.1 "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. March 2001. doi:10.1073/pnas.051633198. PMID 11248043. Bibcode: 2001PNAS...98.3127B. 
  19. ↑ "The conformation of thermolysin". The Journal of Biological Chemistry 249 (24): 8030–44. December 1974. doi:10.1016/S0021-9258(19)42067-X. PMID 4214815. 
  20. ↑ "Mapping sequence differences between thimet oligopeptidase and neurolysin implicates key residues in substrate recognition". Protein Science 11 (9): 2237–46. September 2002. doi:10.1110/ps.0216302. PMID 12192079. 
  21. ↑ "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. September 1994. PMID 7935321. 
  22. ↑ "Novel natural peptide substrates for endopeptidase 24.15, neurolysin, and angiotensin-converting enzyme". The Journal of Biological Chemistry 278 (10): 8547–55. March 2003. doi:10.1074/jbc.M212030200. PMID 12500972. 
  23. ↑ 23.0 23.1 "Pharmacological characterization of a novel non-AT1, non-AT2 angiotensin binding site identified as neurolysin". Endocrine 44 (2): 525–31. October 2013. doi:10.1007/s12020-013-9898-x. PMID 23412923. 
  24. ↑ 24.0 24.1 "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. January 2012. doi:10.1074/jbc.M111.273052. PMID 22039052. 
  25. ↑ 25.0 25.1 "Neurotensin mediates rat bladder mast cell degranulation triggered by acute psychological stress". Urology 53 (5): 1035–40. May 1999. doi:10.1016/s0090-4295(98)00627-x. PMID 10223502. 
  26. ↑ 26.0 26.1 26.2 "Interaction between neurotensin and dopamine in the brain. Morphofunctional and clinical evidence". Annals of the New York Academy of Sciences 668: 217–31. 1992. doi:10.1111/j.1749-6632.1992.tb27352.x. PMID 1361114. 
  27. ↑ 27.0 27.1 "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. September 1997. doi:10.1152/jn.1997.78.3.1341. PMID 9310425. 
  28. ↑ "CSF neurotensin concentrations and antipsychotic treatment in schizophrenia and schizoaffective disorder". The American Journal of Psychiatry 154 (7): 1019–21. July 1997. doi:10.1176/ajp.154.7.1019. PMID 9210757. 
  29. ↑ "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. April 1993. doi:10.1152/ajpheart.1993.264.4.H1062. PMID 8476083. 
  30. ↑ "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. October 1998. PMID 9765351. 
  31. ↑ "Neurobiologic basis of nicotine addiction and psychostimulant abuse: a role for neurotensin?". The Psychiatric Clinics of North America 28 (3): 737–51, 746. September 2005. doi:10.1016/j.psc.2005.05.001. PMID 16122577. 
  32. ↑ "The effects of neuropeptides on discrete-trial conditioned avoidance responding". Brain Research 237 (1): 183–92. April 1982. doi:10.1016/0006-8993(82)90566-2. PMID 6176291. 
  33. ↑ "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. June 1997. doi:10.1038/sj.bjp.0701182. PMID 9208137. 
  34. ↑ "Modulation of cytokine release and gene expression by the immunosuppressive domain of gp41 of HIV-1". PLOS ONE 8 (1): e55199. 2013. doi:10.1371/journal.pone.0055199. PMID 23383108. Bibcode: 2013PLoSO...855199D. 

Further reading

  • "Construction of expression-ready cDNA clones for KIAA genes: manual curation of 330 KIAA cDNA clones". DNA Research 9 (3): 99–106. June 2002. doi:10.1093/dnares/9.3.99. PMID 12168954. 
  • "Characterization of a mitochondrial metallopeptidase reveals neurolysin as a homologue of thimet oligopeptidase". The Journal of Biological Chemistry 270 (5): 2092–8. February 1995. doi:10.1074/jbc.270.5.2092. PMID 7836437. 
  • "Purification and characterization of human endopeptidase 3.4.24.16. Comparison with the porcine counterpart indicates a unique cleavage site on neurotensin". Brain Research 709 (1): 51–8. February 1996. doi:10.1016/0006-8993(95)01260-5. PMID 8869556. 
  • "Stably transfected human cells overexpressing rat brain endopeptidase 3.4.24.16: biochemical characterization of the activity and expression of soluble and membrane-associated counterparts". Journal of Neurochemistry 68 (2): 837–45. February 1997. doi:10.1046/j.1471-4159.1997.68020837.x. PMID 9003076. 
  • "Characterization and localization of mitochondrial oligopeptidase (MOP) (EC 3.4.24.16) activity in the human cervical adenocarcinoma cell line HeLa". Journal of Cellular Biochemistry 66 (3): 297–308. September 1997. doi:10.1002/(SICI)1097-4644(19970901)66:3<297::AID-JCB3>3.0.CO;2-K. PMID 9257187. 
  • "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. September 1998. doi:10.1006/bbrc.1998.8941. PMID 9735321. 
  • "Confocal microscopy reveals thimet oligopeptidase (EC 3.4.24.15) and neurolysin (EC 3.4.24.16) in the classical secretory pathway". DNA and Cell Biology 18 (4): 323–31. April 1999. doi:10.1089/104454999315385. PMID 10235115. 
  • "Bradykinin analogues with beta-amino acid substitutions reveal subtle differences in substrate specificity between the endopeptidases EC 3.4.24.15 and EC 3.4.24.16". Journal of Peptide Science 6 (9): 440–5. September 2000. doi:10.1002/1099-1387(200009)6:9<440::AID-PSC280>3.0.CO;2-K. PMID 11016880. 
  • "Metalloendopeptidases EC 3.4.24.15/16 regulate bradykinin activity in the cerebral microvasculature". American Journal of Physiology. Heart and Circulatory Physiology 284 (6): H1942-8. June 2003. doi:10.1152/ajpheart.00948.2002. PMID 12586639. 
  • "Endopeptidases 3.4.24.15 and 24.16 in endothelial cells: potential role in vasoactive peptide metabolism". American Journal of Physiology. Heart and Circulatory Physiology 284 (6): H1978-84. June 2003. doi:10.1152/ajpheart.01116.2002. PMID 12609826. 
  • "Swapping the substrate specificities of the neuropeptidases neurolysin and thimet oligopeptidase". The Journal of Biological Chemistry 282 (13): 9722–32. March 2007. doi:10.1074/jbc.M609897200. PMID 17251185. 




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