Furin

Last updated
FURIN
Protein FURIN PDB 1p8j.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases FURIN , FUR, PACE, PCSK3, SPC1, furin, paired basic amino acid cleaving enzyme
External IDs OMIM: 136950 MGI: 97513 HomoloGene: 1930 GeneCards: FURIN
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 Mb Chr 7: 80.04 – 80.06 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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

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

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

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

Related Research Articles

<span class="mw-page-title-main">Proteolysis</span> Breakdown of proteins into smaller polypeptides or amino acids

Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, but may also occur by intra-molecular digestion.

<span class="mw-page-title-main">Proopiomelanocortin</span> Mammalian protein found in Homo sapiens

Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.

<span class="mw-page-title-main">Proprotein convertase 1</span>

Proprotein convertase 1, also known as prohormone convertase, prohormone convertase 3, or neuroendocrine convertase 1 and often abbreviated as PC1/3 is an enzyme that in humans is encoded by the PCSK1 gene. PCSK1 and PCSK2 differentially cleave proopiomelanocortin and they act together to process proinsulin and proglucagon in pancreatic islets.

<span class="mw-page-title-main">Sterol regulatory element-binding protein</span> Protein family

Sterol regulatory element-binding proteins (SREBPs) are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. Mammalian SREBPs are encoded by the genes SREBF1 and SREBF2. SREBPs belong to the basic-helix-loop-helix leucine zipper class of transcription factors. Unactivated SREBPs are attached to the nuclear envelope and endoplasmic reticulum membranes. In cells with low levels of sterols, SREBPs are cleaved to a water-soluble N-terminal domain that is translocated to the nucleus. These activated SREBPs then bind to specific sterol regulatory element DNA sequences, thus upregulating the synthesis of enzymes involved in sterol biosynthesis. Sterols in turn inhibit the cleavage of SREBPs and therefore synthesis of additional sterols is reduced through a negative feed back loop.

Proprotein convertases (PPCs) are a family of proteins that activate other proteins. Many proteins are inactive when they are first synthesized, because they contain chains of amino acids that block their activity. Proprotein convertases remove those chains and activate the protein. The prototypical proprotein convertase is furin. Proprotein convertases have medical significance, because they are involved in many important biological processes, such as cholesterol synthesis. Compounds called proprotein convertase inhibitors can block their action, and block the target proteins from becoming active. Many proprotein convertases, especially furin and PACE4, are involved in pathological processes such as viral infection, inflammation, hypercholesterolemia, and cancer, and have been postulated as therapeutic targets for some of these diseases.

<span class="mw-page-title-main">Proprotein convertase 2</span> Protein-coding gene in the species Homo sapiens

Proprotein convertase 2 (PC2) also known as prohormone convertase 2 or neuroendocrine convertase 2 (NEC2) is a serine protease and proprotein convertase PC2, like proprotein convertase 1 (PC1), is an enzyme responsible for the first step in the maturation of many neuroendocrine peptides from their precursors, such as the conversion of proinsulin to insulin intermediates. To generate the bioactive form of insulin, a second step involving the removal of C-terminal basic residues is required; this step is mediated by carboxypeptidases E and/or D. PC2 plays only a minor role in the first step of insulin biosynthesis, but a greater role in the first step of glucagon biosynthesis compared to PC1. PC2 binds to the neuroendocrine protein named 7B2, and if this protein is not present, proPC2 cannot become enzymatically active. 7B2 accomplishes this by preventing the aggregation of proPC2 to inactivatable forms. The C-terminal domain of 7B2 also inhibits PC2 activity until it is cleaved into smaller inactive forms that lack carboxy-terminal basic residues. Thus, 7B2 is both an activator and an inhibitor of PC2. PC2 has been identified in a number of animals, including C. elegans.

<span class="mw-page-title-main">Hemojuvelin</span>

Hemojuvelin (HJV), also known as repulsive guidance molecule C (RGMc) or hemochromatosis type 2 protein (HFE2), is a membrane-bound and soluble protein in mammals that is responsible for the iron overload condition known as juvenile hemochromatosis in humans, a severe form of hemochromatosis. In humans, the hemojuvelin protein is encoded by the HFE2 gene. Hemojuvelin is a member of the repulsive guidance molecule family of proteins. Both RGMa and RGMb are found in the nervous system, while hemojuvelin is found in skeletal muscle and the liver.

<span class="mw-page-title-main">Sterol regulatory element-binding protein 2</span> Protein-coding gene in the species Homo sapiens

Sterol regulatory element-binding protein 2 (SREBP-2) also known as sterol regulatory element binding transcription factor 2 (SREBF2) is a protein that in humans is encoded by the SREBF2 gene.

<span class="mw-page-title-main">PCSK9</span> Mammalian protein found in humans

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">Membrane-bound transcription factor site-1 protease</span> Mammalian protein found in Homo sapiens

Membrane-bound transcription factor site-1 protease, or site-1 protease (S1P) for short, also known as subtilisin/kexin-isozyme 1 (SKI-1), is an enzyme that in humans is encoded by the MBTPS1 gene. S1P cleaves the endoplasmic reticulum loop of sterol regulatory element-binding protein (SREBP) transcription factors.

Kexin is a prohormone-processing protease, specifically a yeast serine peptidase, found in the budding yeast. It catalyzes the cleavage of -Lys-Arg- and -Arg-Arg- bonds to process yeast alpha-factor pheromone and killer toxin precursors. The human homolog is PCSK4. It is a family of subtilisin-like peptidases. Even though there are a few prokaryote kexin-like peptidases, all kexins are eukaryotes. The enzyme is encoded by the yeast gene KEX2, and usually referred to in the scientific community as Kex2p. It shares structural similarities with the bacterial protease subtilisin. The first mammalian homologue of this protein to be identified was furin. In the mammal, kexin-like peptidases function in creating and regulating many differing proproteins.

<span class="mw-page-title-main">Cathepsin L1</span> Protein-coding gene in the species Homo sapiens

Cathepsin L1 is a protein that in humans is encoded by the CTSL1 gene. The protein is a cysteine cathepsin, a lysosomal cysteine protease that plays a major role in intracellular protein catabolism.

<span class="mw-page-title-main">PMEL (gene)</span> Protein-coding gene in the species Homo sapiens

Melanocyte protein PMEL also known as premelanosome protein (PMEL), silver locus protein homolog (SILV) or Glycoprotein 100 (gp100), is a protein that in humans is encoded by the PMEL gene. Its gene product may be referred to as PMEL, silver, ME20, gp100 or Pmel17.

<span class="mw-page-title-main">PCSK5</span> Protein-coding gene in the species Homo sapiens

Proprotein convertase subtilisin/kexin type 5 is an enzyme that in humans is encoded by the PCSK5 gene, found in chromosome 9q21.3 Two alternatively spliced transcripts are described for this gene but only one has its full length nature known.

<span class="mw-page-title-main">PCSK7</span> Protein-coding gene in the species Homo sapiens

Proprotein convertase subtilisin/kexin type 7 is an enzyme that in humans is encoded by the PCSK7 gene.

<span class="mw-page-title-main">PCSK6</span> Protein-coding gene in the species Homo sapiens

Proprotein convertase subtilisin/kexin type 6 is an protease that in humans is encoded by the PCSK6 gene which is located in chromosome 15. Pcsk6 is a calcium-dependent serine endoprotease that catalyzes the post-translational modification of precursor proteins from its ‘latent’ form to the cleaved ‘active’ form. Active Pcsk6 has been reported to process substrates such as transforming growth factor β, pro-albumin, von Willebrand factor, and corin. Clinically, Pcsk6 is suggested to play a role in left/right asymmetry, structural asymmetry of the brain, handedness, tumor progression, hemostasis, and cardiovascular diseases.

<span class="mw-page-title-main">PCSK4</span> Protein-coding gene in the species Homo sapiens

Proprotein convertase subtilisin/kexin type 4 is an enzyme that in humans is encoded by the PCSK4 gene.

<span class="mw-page-title-main">Subtilase</span>

Subtilases are a family of subtilisin-like serine proteases. They appear to have independently and convergently evolved an Asp/Ser/His catalytic triad, like in the trypsin serine proteases. The structure of proteins in this family shows that they have an alpha/beta fold containing a 7-stranded parallel beta sheet.

<span class="mw-page-title-main">Aureolysin</span>

Aureolysin is an extracellular metalloprotease expressed by Staphylococcus aureus. This protease is a major contributor to the bacterium's virulence, or ability to cause disease, by cleaving host factors of the innate immune system as well as regulating S. aureus secreted toxins and cell wall proteins. To catalyze its enzymatic activities, aureolysin requires zinc and calcium which it obtains from the extracellular environment within the host.

<span class="mw-page-title-main">Collagen, type XXIII, alpha 1</span> Mammalian protein found in humans

Collagen α-1 (XXIII) chain is a protein encoded by COL23A1 gene, which is located on chromosome 5q35 in humans, and on chromosome 11B1+2 in mice. The location of this gene was discovered by genomic sequence analysis.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000140564 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 "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.

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