Neutrophil elastase

In today's world, Neutrophil elastase has become a topic of utmost importance and relevance for different areas and sectors. Its impact has been notable in society, the economy, politics, culture and in people's daily lives. Since its emergence, Neutrophil elastase has generated endless debates, discussions and analyzes that have allowed us to understand its scope and impact in today's world. In this article, we will explore in detail the different edges and aspects related to Neutrophil elastase, analyzing its evolution over time, its current implications and challenges, as well as its possible future developments. It will examine how Neutrophil elastase has transformed the way we think, act and relate, as well as the opportunities and challenges it represents for the future.

ELANE
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesELANE, ELA2, GE, HLE, HNE, NE, PMN-E, SCN1, elastase, neutrophil expressed
External IDsOMIM: 130130; MGI: 2679229; HomoloGene: 20455; GeneCards: ELANE; OMA:ELANE - orthologs
Orthologs
SpeciesHumanMouse
Entrez

1991

50701

Ensembl

ENSG00000277571
ENSG00000197561

ENSMUSG00000020125

UniProt

P08246

Q3UP87

RefSeq (mRNA)

NM_001972

NM_015779

RefSeq (protein)

NP_001963

NP_056594

Location (UCSC)Chr 19: 0.85 – 0.86 MbChr 10: 79.72 – 79.72 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Neutrophil elastase (EC 3.4.21.37, leukocyte elastase, ELANE, ELA2, elastase 2, neutrophil, elaszym, serine elastase, subtype human leukocyte elastase (HLE)) is a serine proteinase in the same family as chymotrypsin and has broad substrate specificity. Neutrophil elastase is secreted by neutrophils during inflammation, and destroys bacteria and host tissue.[5] It also localizes to neutrophil extracellular traps (NETs), via its high affinity for DNA, an unusual property for serine proteases.[6]

As with other serine proteinases it contains a charge relay system composed of the catalytic triad of histidine, aspartate, and serine residues that are dispersed throughout the primary sequence of the polypeptide but that are brought together in the three dimensional conformation of the folded protein. The gene encoding neutrophil elastase, ELA2, consists of five exons. Neutrophil elastase is closely related to other cytotoxic immune serine proteases, such as the granzymes and cathepsin G. It is more distantly related to the digestive CELA1.[6]

The neutrophil form of elastase (EC 3.4.21.37) is 218 amino acids long, with two asparagine-linked carbohydrate chains (see glycosylation). It is present in azurophil granules in the neutrophil cytoplasm. There appear to be two forms of neutrophil elastase, termed IIa and IIb.

Gene

In humans, neutrophil elastase is encoded by the ELANE gene, which resides on chromosome 11.[7]

Function

Elastases form a subfamily of serine proteases that hydrolyze many proteins in addition to elastin. Humans have six elastase genes that encode the structurally similar proteins elastase 1, 2, 2A, 2B, 3A, and 3B. Neutrophil elastase hydrolyzes proteins within specialized neutrophil lysosomes, called azurophil granules, as well as proteins of the extracellular matrix following the protein's release from activated neutrophils. Neutrophil elastase may play a role in degenerative and inflammatory diseases by its proteolysis of collagen-IV and elastin of the extracellular matrix. This protein degrades the outer membrane protein A (OmpA) of E. coli as well as the virulence factors of such bacteria as Shigella, Salmonella and Yersinia.[8] Mutations in this gene are associated with cyclic neutropenia (CyN) and severe congenital neutropenia (SCN). At least 95 disease-causing mutations in this gene have been discovered.[9] This gene is clustered with other serine protease gene family members, azurocidin 1 and proteinase 3 genes, at chromosome 19pter. All 3 genes are expressed coordinately and their protein products are packaged together into azurophil granules during neutrophil differentiation.[10]

Clinical significance

Neutrophil elastase is an important protease enzyme that when expressed aberrantly can cause emphysema or emphysematous changes. This involves breakdown of the lung structure and increased airspaces. Mutations of the ELANE gene cause cyclic and severe congenital neutropenia, which is a failure of neutrophils to mature.[11] In 2019 study was confirmed that ELANE deletion does not cause neutropenia.[12]

Inhibitors

In order to minimize damage to tissues, there are few inhibitors of neutrophil elastase. One group of inhibitors are the Serpins (Serine Protease Inhibitors).[13] Neutrophil elastase has been shown to interact with Alpha 2-antiplasmin, which belongs to the Serpin family of proteins.[14][15]

See also

References

  1. ^ a b c ENSG00000197561 GRCh38: Ensembl release 89: ENSG00000277571, ENSG00000197561 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000020125 – 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. ^ Belaaouaj A, Kim KS, Shapiro SD (August 2000). "Degradation of outer membrane protein A in Escherichia coli killing by neutrophil elastase". Science. 289 (5482): 1185–8. Bibcode:2000Sci...289.1185B. doi:10.1126/science.289.5482.1185. PMID 10947984.
  6. ^ a b Thomas MP, Whangbo J, McCrossan G, Deutsch AJ, Martinod K, Walch M, Lieberman J (June 2014). "Leukocyte protease binding to nucleic acids promotes nuclear localization and cleavage of nucleic acid binding proteins". J. Immunol. 192 (11): 5390–7. doi:10.4049/jimmunol.1303296. PMC 4041364. PMID 24771851.
  7. ^ Takahashi H, Nukiwa T, Yoshimura K, Quick CD, States DJ, Holmes MD, Whang-Peng J, Knutsen T, Crystal RG (October 1988). "Structure of the human neutrophil elastase gene". J. Biol. Chem. 263 (29): 14739–47. doi:10.1016/S0021-9258(18)68099-8. PMID 2902087.
  8. ^ Weinrauch Y, Drujan D, Shapiro SD, Weiss J, Zychlinsky A (May 2002). "Neutrophil elastase targets virulence factors of enterobacteria". Nature. 417 (6884): 91–4. Bibcode:2002Natur.417...91W. doi:10.1038/417091a. PMID 12018205. S2CID 4341470.
  9. ^ Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.
  10. ^ "Entrez Gene: ELA2 elastase 2, neutrophil".
  11. ^ Dale DC, Link DC (January 2009). "The many causes of severe congenital neutropenia". N. Engl. J. Med. 360 (1): 3–5. doi:10.1056/NEJMp0806821. PMC 4162527. PMID 19118300.
  12. ^ Horwitz MS, Laurino MY, Keel SB (August 2019). "ELANE whole gene deletion mutation". Blood Advances. 3 (16): 2470–2473. doi:10.1182/bloodadvances.2019000498. PMC 6712528. PMID 31427279.
  13. ^ Korkmaz B, Horwitz MS, Jenne DE, Gauthier F (December 2010). "Neutrophil elastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases". Pharmacol. Rev. 4 (62): 726–59. doi:10.1124/pr.110.002733. PMC 2993259. PMID 21079042.
  14. ^ Brower MS, Harpel PC (August 1982). "Proteolytic cleavage and inactivation of alpha 2-plasmin inhibitor and C1 inactivator by human polymorphonuclear leukocyte elastase". J. Biol. Chem. 257 (16): 9849–54. doi:10.1016/S0021-9258(18)34149-8. PMID 6980881.
  15. ^ Shieh BH, Travis J (May 1987). "The reactive site of human alpha 2-antiplasmin". J. Biol. Chem. 262 (13): 6055–9. doi:10.1016/S0021-9258(18)45536-6. PMID 2437112.

Further reading