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Furin

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FURIN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesFURIN, FUR, PACE, PCSK3, SPC1, furin, paired basic amino acid cleaving enzyme
External IDsOMIM: 136950; MGI: 97513; HomoloGene: 1930; GeneCards: FURIN; OMA:FURIN - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5045

18550

Ensembl

ENSG00000140564

ENSMUSG00000030530

UniProt

P09958

P23188

RefSeq (mRNA)

NM_002569
NM_001289823
NM_001289824

NM_001081454
NM_011046

RefSeq (protein)

NP_001074923
NP_035176

Location (UCSC)Chr 15: 90.87 – 90.88 MbChr 7: 80.04 – 80.06 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Furin is a protease, a proteolytic enzyme activated by substrate presentation that in humans and other animals is encoded by the FURIN gene. Some proteins are inactive when they are first synthesized, and must have sections removed in order to become active. Furin cleaves these sections and activates the proteins.[5][6][7][8] It was named furin because it was in the upstream region of an oncogene known as FES. The gene was known as FUR (FES Upstream Region) and therefore the protein was named furin. Furin is also known as PACE (Paired basic Amino acid Cleaving Enzyme). A member of family S8, furin is a subtilisin-like peptidase.

Function

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The protein encoded by this gene is an enzyme that belongs to the subtilisin-like proprotein convertase family. The members of this family are proprotein convertases that process latent precursor proteins into their biologically active products. This encoded protein is a calcium-dependent serine endoprotease that can efficiently cleave precursor proteins at their paired basic amino acid processing sites. Some of its substrates are: proparathyroid hormone, transforming growth factor beta 1 precursor, proalbumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, beta subunit of pro-nerve growth factor and von Willebrand factor. A furin-like pro-protein convertase has been implicated in the processing of RGMc (also called hemojuvelin), a gene involved in a severe iron-overload disorder called juvenile hemochromatosis. Both the Ganz and Rotwein groups demonstrated that furin-like proprotein convertases (PPC) are responsible for conversion of 50 kDa HJV to a 40 kDa protein with a truncated COOH-terminus, at a conserved polybasic RNRR site. This suggests a potential mechanism to generate the soluble forms of HJV/hemojuvelin (s-hemojuvelin) found in the blood of rodents and humans.[9][10]

The furin substrates and the locations of furin cleavage sites in protein sequences can be predicted by two bioinformatics methods: ProP[11] and PiTou.[12]

Clinical significance

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Furin is one of the proteases responsible for the proteolytic cleavage of HIV envelope polyprotein precursor gp160 to gp120 and gp41 prior to viral assembly.[13] This protease is also thought to play a role in tumor progression.[7] The use of alternate polyadenylation sites has been found for the FURIN gene.[citation needed]

Furin is enriched in the Golgi apparatus, where it functions to cleave other proteins into their mature/active forms.[14] Furin cleaves proteins just downstream of a basic amino acid target sequence (canonically, Arg-X-(Arg/Lys) -Arg'). In addition to processing cellular precursor proteins, furin is also used by a number of pathogens. For example, the envelope proteins of viruses such as HIV, influenza, dengue fever, several filoviruses including ebola and marburg virus, and the spike protein of SARS-CoV-2,[15][16][17] must be cleaved by furin or furin-like proteases to become fully functional. When SARS-CoV-2 virus is being synthesized in an infected cell, furin or furin-like proteases cleave the spike protein into two portions (S1 and S2), which remain associated.[18]

Anthrax toxin, Pseudomonas exotoxin, and papillomaviruses must be processed by furin during their initial entry into host cells. Inhibitors of furin are under consideration as therapeutic agents for treating anthrax infection.[19]

Furin is regulated by cholesterol and substrate presentation. When cholesterol is high, furin traffics to GM1 lipid rafts. When cholesterol is low, furin traffics to the disordered region.[20] This is speculated to contribute to cholesterol and age dependent priming of SARS-CoV.

Expression of furin in T-cells is required for maintenance of peripheral immune tolerance.[21]

Interactions

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Furin has been shown to interact with PACS1.[22]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000140564 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030530 – 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. ^ Wise RJ, Barr PJ, Wong PA, Kiefer MC, Brake AJ, Kaufman RJ (December 1990). "Expression of a human proprotein processing enzyme: correct cleavage of the von Willebrand factor precursor at a paired basic amino acid site". Proceedings of the National Academy of Sciences of the United States of America. 87 (23): 9378–82. Bibcode:1990PNAS...87.9378W. doi:10.1073/pnas.87.23.9378. PMC 55168. PMID 2251280.
  6. ^ Kiefer MC, Tucker JE, Joh R, Landsberg KE, Saltman D, Barr PJ (December 1991). "Identification of a second human subtilisin-like protease gene in the fes/fps region of chromosome 15". DNA and Cell Biology. 10 (10): 757–69. doi:10.1089/dna.1991.10.757. PMID 1741956.
  7. ^ a b "Entrez Gene: FURIN furin (paired basic amino acid cleaving enzyme)".
  8. ^ Roebroek AJ, Schalken JA, Leunissen JA, Onnekink C, Bloemers HP, Van de Ven WJ (September 1986). "Evolutionary conserved close linkage of the c-fes/fps proto-oncogene and genetic sequences encoding a receptor-like protein". The EMBO Journal. 5 (9): 2197–202. doi:10.1002/j.1460-2075.1986.tb04484.x. PMC 1167100. PMID 3023061.
  9. ^ Lin L, Nemeth E, Goodnough JB, Thapa DR, Gabayan V, Ganz T (2008). "Soluble hemojuvelin is released by proprotein convertase-mediated cleavage at a conserved polybasic RNRR site". Blood Cells, Molecules & Diseases. 40 (1): 122–31. doi:10.1016/j.bcmd.2007.06.023. PMC 2211380. PMID 17869549.
  10. ^ Kuninger D, Kuns-Hashimoto R, Nili M, Rotwein P (April 2008). "Pro-protein convertases control the maturation and processing of the iron-regulatory protein, RGMc/hemojuvelin". BMC Biochemistry. 9: 9. doi:10.1186/1471-2091-9-9. PMC 2323002. PMID 18384687.
  11. ^ Duckert P, Brunak S, Blom N (January 2004). "Prediction of proprotein convertase cleavage sites". Protein Engineering, Design & Selection. 17 (1): 107–12. doi:10.1093/protein/gzh013. PMID 14985543.
  12. ^ Tian S, Huajun W, Wu J (February 2012). "Computational prediction of furin cleavage sites by a hybrid method and understanding mechanism underlying diseases". Scientific Reports. 2: 261. Bibcode:2012NatSR...2E.261T. doi:10.1038/srep00261. PMC 3281273. PMID 22355773.
  13. ^ Hallenberger S, Bosch V, Angliker H, Shaw E, Klenk HD, Garten W (November 1992). "Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160". Nature. 360 (6402): 358–61. Bibcode:1992Natur.360..358H. doi:10.1038/360358a0. PMID 1360148. S2CID 4306605.
  14. ^ Thomas G (October 2002). "Furin at the cutting edge: from protein traffic to embryogenesis and disease". Nature Reviews. Molecular Cell Biology. 3 (10): 753–66. doi:10.1038/nrm934. PMC 1964754. PMID 12360192.
  15. ^ Coutard B, Valle C, de Lamballerie X, Canard B, Seidah NG, Decroly E (April 2020). "The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade". Antiviral Research. 176: 104742. doi:10.1016/j.antiviral.2020.104742. PMC 7114094. PMID 32057769.
  16. ^ Hoffmann M, Kleine-Weber H, Pöhlmann S (May 2020). "A Multibasic Cleavage Site in the Spike Protein of SARS-CoV-2 Is Essential for Infection of Human Lung Cells". Molecular Cell. 78 (4): 779–784.e5. doi:10.1016/j.molcel.2020.04.022. PMC 7194065. PMID 32362314.
  17. ^ "The origin of COVID-19: Evidence piles up, but the jury's still out". 11 October 2021. The furin cleavage site on the SARS-CoV-2 virus allows its spikes to be cut and "primed" as it moves out of one cell and into another. The site is thought to make the virus more transmissible.
  18. ^ Jackson CB, Farzan M, Chen B, Choe H (2022). "Mechanisms of SARS-CoV-2 entry into cells". Nature Reviews Molecular Cell Biology. 23 (1): 3–20. doi:10.1038/s41580-021-00418-x. PMC 8491763. PMID 34611326.
  19. ^ Shiryaev SA, Remacle AG, Ratnikov BI, Nelson NA, Savinov AY, Wei G, et al. (July 2007). "Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens". The Journal of Biological Chemistry. 282 (29): 20847–53. doi:10.1074/jbc.M703847200. PMID 17537721.
  20. ^ Wang H, Yuan Z, Pavel MA, Jablonski SM, Jablonski J, Hobson R, et al. (June 2021). "The role of high cholesterol in age-related COVID19 lethality". bioRxiv: 2020.05.09.086249. doi:10.1101/2020.05.09.086249. PMC 7263494. PMID 32511366.
  21. ^ Pesu M, Watford WT, Wei L, Xu L, Fuss I, Strober W, et al. (September 2008). "T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance". Nature. 455 (7210): 246–50. Bibcode:2008Natur.455..246P. doi:10.1038/nature07210. PMC 2758057. PMID 18701887.
  22. ^ Wan L, Molloy SS, Thomas L, Liu G, Xiang Y, Rybak SL, Thomas G (July 1998). "PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans-Golgi network localization". Cell. 94 (2): 205–16. doi:10.1016/S0092-8674(00)81420-8. PMID 9695949. S2CID 15027198.

Further reading

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