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evolution
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molecular evolution of enzyme function in the proprotein convertase family, overview
evolution
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PC members are paralogous genes derived from a common ancestor, which represents independent lineages by gene replication in evolution. Abalone PC1 is located in PC1 clade which is orthologous genes in different species. The potential cleavage site delineating the pro-domain, Arg102-Xaa-Lys-Arg, is remarkably conserved among different species and is preceded by two preserved Gln residues located in positions 96 and 97
evolution
furin is a member of the pro-hormone/pro-protein convertase family of subtilisin-like endoproteinases
evolution
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furin is a member of the proprotein convertase family
evolution
furin is a member of the proprotein convertase family
evolution
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furin is a member of the subtilisin-like proteases and belongs to the proprotein convertase subtilisin/kexin-like proteases, subgroup PCSK3
evolution
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phylogenetic analysis and sequence comparisons. Differences may exist between furin proteases present in fruit bats compared to furins in other mammalian species, and these differences may impact protease usage for viral glycoprotein processing. Subtle differences in cellular distribution and localization of furin or trafficking through trans-Golgi network may exist between different mammalian species
evolution
the enzyme belongs to the family of serine proteases
evolution
the enzyme belongs to the proprotein convertase family of proteases
evolution
the enzyme is a member of the subtilisin-like proprotein convertase family
evolution
four of nine conserved proprotein convertases (PCs), including furin, Pace4, PC5A/B, and PC7, cleave substrates after the minimal dibasic recognition motif (K/R)-(X)n-(K/R)Y, where n is 0, 2, 4, or 6 and X can be any amino acid. In 152 PC sequences examined across species, the catalytic sites are 95% identical
evolution
furin belongs to the family of Ca2+-dependent proprotein convertases (PCs), all of which contain a subtilisin-like serine protease domain. Furin and the other six basic PCs, i.e. PC1, PC2, PC4, PACE4, PC5, and PC7, cleave their substrates at multibasic sequences mainly after arginine, whereas the nonbasic PC site-1 protease (S1P) cleaves preferentially after leucine, valine, or isoleucine
evolution
furin belongs to the proprotein convertase subtilisin/kexin (PCSK) family of enzymes play a crucial role in processing and trafficking of a wide variety of precursor proteins such as hormones, receptors, and enzymes
evolution
furin is a member of the prototypical PC family
malfunction
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blockade of furin activity and furin-induced tumor cells malignant phenotypes by the chemically synthesized human furin prodomain, overview
malfunction
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furin inhibition leads to a 38% reduction of oocyte release from ovaries, overview
malfunction
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furin is involved in many physiological and pathological processes
malfunction
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furin is linked to cancer, tumorgenesis, and viral and bacterial pathogenesis
malfunction
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furin or a furin-like proprotein convertase facilitates duck hepatitis B virus, DHBV, infection by cleaving both the docking receptor and the viral large envelope protein
malfunction
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inhibition of furin inhibits processing of pro-B-type natriuretic peptide
malfunction
ablation of productive infectious bronchitis virus, IBV, infection by knockdown of furin expression in H1299 cells
malfunction
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furin inhibition reduces brain-derived neurotrophic factor maturation and secretion
malfunction
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furin siRNA significantly increases apoptosis of the granulosa cells from large antral/preovulatory follicles, in part via downregulation of the anti-apoptotic proteins, XIAP and p-AKT. On the contrary, furin siRNA markedly decreases proliferation of granulosa cells based on the downregulation of proliferation cell nuclear antigen
malfunction
furin siRNAs upregulate HIF-1alpha protein under normoxic condition to a level similar to that obtained by cobalt chloride treatment, eventually leading to activation of VEGF-A synthesis in two human head and neck squamous cell carcinoma cell lines. HIF-1alpha induction of the enzyme siRNAs and either cobalt chloride or the 26S ribosome inhibitor, MG-132, suggesting a post-transcriptional enzyme-mediated regulation, the induction by siRNAs is inhibited by a specific IGF-1R signaling inhibitor
malfunction
furin-specific siRNAs or inhibitors inhibit cell fusion in choriocarcinoma BeWo cells, as well as trophoblast syncytialization in human placental explants
malfunction
knockdown of the enzyme expression in C8161.9, MelJuSo, and HeLa cells by shRNA leads to reduced or complete loss of KISS1 processing
malfunction
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placenta-specific knockdown of furin in the mouse leads to severe defects in syncytialization and embryonic lethality, phenotype, overview
malfunction
an unbalanced activity of proprotein convertases is connected to pathologies like cancer, atherosclerosis, hypercholesterolaemia, and infectious diseases
malfunction
dysregulation of furin is implicated in numerous disease states, including cancer and fibrosis
malfunction
interleukin-2 is increased initially in furin-deficient mouse CD4+ T cells, but the T-cell receptor-induced interleukin-2 mRNA expression is not sustained in the absence of furin. Conditional deletion of FURIN in CD4+ T-cells leads to hyperactive T-cells and the overproduction of Th1 and Th2 cytokines and systemic autoimmunity as a result of the loss of Treg-mediated immunologic tolerance
malfunction
plant-produced human furin treated with PNGase F and Endo H does not exhibit cleavage activity. Similarly, when commercial human furin (NEB) is treated with commercial Endo H or PNGase F, no cleavage is observed for the substrate PA83
malfunction
Sema3B acts as a tumor suppressor in lung cancer and inhibits the formation of endothelial cells tubes in an in vitro angiogenesis. This function is abrogated upon mutation at the furin cleavage site. The C-terminal arginine of the putative furin cleavage site at the basic domain of Sema3C protein is critical for its functions in angiogenesis process
malfunction
the inhibition of furin in human Jurkat T cell lines also results in a decrease in interleukin-2 production, whereas the overexpression of wild-type furin is associated with elevated interleukin-2 levels
malfunction
the PLC motif in the cytosolic tail of proprotein convertase 7 (PC7) is dispensable for endosomal activity, but it is specifically required for trans-Golgi network (TGN) recycling and to rescue proactivin-A cleavage in furin-depleted B16-F1 melanoma cells. PC7 complements furin in cleaving Notch1 independently of PLC-mediated TGN access
malfunction
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furin inhibition reduces brain-derived neurotrophic factor maturation and secretion
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metabolism
cellular furin content might be a potential factor determining the susceptibility of cultured human and animal cells to coronavirus infectious bronchitis virus infection
metabolism
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the enzyme activates large numbers of proprotein substrates and is ubiquitously expressed and implicated in many physiological and pathological processes
metabolism
all proprotein convertase (PC) activity detected in the trans-Golgi network/endosomal system of B16-F1 cells is mediated by furin, but not by endogenous PC7
metabolism
furin promotes the activation of T cell receptor-induced transcription factors
metabolism
furin-dependent transactivators in different mouse CD4+ T-cell subsets, overview
physiological function
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bone morphogenetic proteins, BMPs, require proteolytic activation by members of the proprotein convertase family
physiological function
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furin activation of the C-terminus of Sema3F produces a species that potently inhibits the binding of VEGF to neuropilin, the C-terminal neuropilin binding region of human Sema3F comprises residues 605-785. Furin processing of semaphorin 3F determines its anti-angiogenic activity by regulating direct binding and competition for neuropilin, mechanism, overview
physiological function
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furin and related proprotein convertases cleave the multibasic motifs R-X-R/K/X-R in the precursor proteins and, as a result, transform the latent proproteins into biologically active proteins and peptides
physiological function
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furin cleavage of CD109 is necessary for its biological activity, CD109 negatively regulates transforming growth factor-beta signaling in keratinocytes by directly modulating receptor activity. Processing of CD109 into 180 kDa and 25kDa proteins by furin, followed by complex formation with the type I TGF-beta receptor is required for the regulation of TGF-beta signaling in cancer cells and keratinocytes
physiological function
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furin is involved in many physiological and pathological processes, it plays a role in human trophoblast invasion and migration
physiological function
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furin is responsible for the shedding of the endogenous (pro)renin receptor, (P)RR, it generates the soluble form of (P)RR, in cultured cells
physiological function
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furin is responsible for the shedding of the endogenous (pro)renin receptor, (P)RR, it generates the soluble form of (P)RR, in cultured cells
physiological function
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furin is responsible for the shedding of the endogenous (pro)renin receptor, (P)RR, it generates the soluble form of (P)RR, in cultured cells
physiological function
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proprotein convertase FurinA plays a role in zebrafish fin development and cell surface shedding of Fras1 and Frem2, large basement membrane proteins, thereby allowing proper localization of the proteins within the basement membrane of forming fins, mechanisms of basement membrane anchorage, overview
physiological function
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the bioluminescence emission in the presence of firefly luciferase is furin-dependent and specific, furin activates the luciferase activity 30fold
physiological function
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the bioluminescence emission in the presence of firefly luciferase is furin-dependent and specific, furin activates the luciferase activity 7fold
physiological function
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the enzyme plays a key role in the posttranslational processing of precursors for bioactive peptides
physiological function
expression of Dfurin1 enhances Sindbis virus titers in RPE.40 cells by a factor of 100-1000, and this increase correlates with efficient cleavage of PE2 glycoprotein
physiological function
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furin is involved in processing of bone morphogenetic protein BMP10. Processing occurs mostly intracellularly, but also at the cell surface
physiological function
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furin serves as an intermolecular chaperone for matrix metalloprotease MMP-28 secretion by interacting with the propeptide domain of MMP-28. cleavage of MMP-28 at the furin consensus sequence does not occur and proteolytic inactive furin is equally effective in enhancing MMP-28 secretion
physiological function
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hypoxia triggers relocalization of furin from the trans-Golgi network to endosomomal compartments and the cell surface in cancer cells. Exposing these cells back to normoxic conditions reverses furin redistribution, suggesting that the tumor microenvironment modulates furin trafficking in a highly regulated manner. Both Rab4GTPase-dependent recycling and interaction of furin with the cytoskeletal anchoring protein, filami A, are essential for the cell surface relocalization of furin. Interference with the association of furin with filamin A, prevents cell surface relocalization of furin and abolishes the ability of cancer cells to migrate in response to hypoxia
physiological function
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in mice lacking furin in hepatocytes, the PCSK9-inactivated form is strongly reduced. Full-length, membrane-bound, but not soluble, furin is the cognate convertase which inactivates PCSK9 by cleavage at R218
physiological function
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fruit bat cells have homologues of cathepsin and furin proteases capable of cleaving and activating both the cathepsin-dependent Hendra virus F and the furin-dependent parainfluenza virus 5 F proteins, involvement of a furin protease in the cleavage of the PIV5 fusion protein, overview
physiological function
furin cleavage of the Moloney murine leukemia virus Env precursor reorganizes the spike structure, overview
physiological function
furin is involved in the secretory pathway. It is the major proprotein convertase required for KISS1-to-kisspeptin processing. KISS1 is a broadly functional secreted proprotein that is then processed into small peptides, termed kisspeptins
physiological function
furin is the major processing protease of the secretory pathway. GPR107 localizes to the trans-Golgi network and is essential for retrograde transport. It is cleaved by the endoprotease furin
physiological function
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furin is upregulated and cleaves certain substrates during hypoxia in cancer cells, the enzyme mediates brain-derived neurotrophic factor upregulation in cultured rat astrocytes exposed to oxygen-glucose deprivation. Maturation of brain-derived neurotrophic factor in astrocytes requires furin-mediated endoproteolytic processing of the precursor protein pro-brain-derived neurotrophic factor to brain-derived neurotrophic factor
physiological function
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furin may play an important role in regulating apoptosis and proliferation of granulosa cells, role of furin in the development of granulosa cells during folliculogenesis, overview
physiological function
furin mediates maturation of bone morphogenetic protein-4
physiological function
regulation of HIF-1 alpha, a major transcription factor involved in tumorigenesis by sensing intratumoral hypoxia, by the proprotein convertases furin and PC7 in human squamous carcinoma cells, overview. Furin is one of the numerous target genes regulated by HIF-1alpha transactivation and its distribution into endosomal compartments and onto the cell surface can be triggered by hypoxia via HIF-1alpha, overview
physiological function
the enzyme is necessary to promote the formation of higher order dendritic branches in PVD mechanosensory neurons and to ensure self-avoidance of sister branches, but is likely not required during maintenance of dendritic arbors. The enzyme also regulates the development of other neurons in all major neuronal classes in Caenorhabditis elegans, including aspects of branching and extension of neurites as well as cell positioning. The enzyme functions in a pathway with MNR-1/menorin, SAX-7/L1CAM and DMA-1 to control dendritic branch formation and extension of PVD neurons. The enzyme acts in concert with the menorin pathway to control branching and growth of somatosensory dendrites in PVD
physiological function
the furin expression level is directly proportional to the efficiency of hemagglutinin cleavage, with implications for viral spread in the host, activation mechanism of avian influenza virus H9N2 by furin, overview
physiological function
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the multinucleated syncytial trophoblast, which forms the outermost layer of the placenta and serves multiple functions, is differentiated from and maintained by cytotrophoblast cell fusion. Cytotrophoblast cell fusion and syncytialization are accompanied by furin expression. Processing of type 1 IGF receptor by furin is an essential mechanism for syncytialization. Furin function is required for the development of syncytiotrophoblast structure in the labyrinth layer, as well as for normal embryonic development
physiological function
the multinucleated syncytial trophoblast, which forms the outermost layer of the placenta and serves multiple functions, is differentiated from and maintained by cytotrophoblast cell fusion. Cytotrophoblast cell fusion and syncytialization are accompanied by furin expression. Processing of type 1 IGF receptor by furin is an essential mechanism for syncytialization. Furin function is required for the development of syncytiotrophoblast structure in the labyrinth layer, as well as for normal embryonic development
physiological function
activation of viral glycoproteins or bacterial toxins, furin and other PCs contribute to the propagation of certain pathogenic viruses and to the toxicity of some bacteria
physiological function
CRISPR editing reveals that both furin and PC7 are functional in B16-F1 cells and able to substitute for each other during Notch1 and ADAM10 precursor processing
physiological function
furin is a calcium-dependent serine endoprotease that processes a wide variety of proproteins involved in cell function and homeostasis
physiological function
furin is a ubiquitous proprotein convertase that is involved in the processing (activation) of a wide variety of precursor proteins, including blood coagulation factors, cell surface receptors, hormones and growth factors, viral envelope glycoproteins, etc. and plays a critical regulatory role in a wide variety of cellular events
physiological function
morula compaction and inner cell mass formation depend on PC7 and the related proteases Furin and Pace4. These proteases jointly regulate cell-cell adhesion mediated by E-cadherin processing during blastocyst formation
physiological function
proprotein convertase furin is a highly specific serine protease modifying and thereby activating proteins in the secretory pathway by proteolytic cleavage. Its substrates are involved in many diseases, including cancer and infections caused by bacteria and viruses
physiological function
proprotein convertase substilisin/kexin-type (PCSK) enzymes regulate proprotein maturation by catalyzing the proteolytic cleavage of their substrates. The prototype PCSK furin is induced upon T cell receptor (TCR) activation, and its expression in T cells is critical for the maintenance of peripheral immune tolerance. Proprotein convertase furin regulates T cell receptor-induced transactivation. TGF-beta1 and NOTCH1 are synthesized initially as inactive precursors and are proteolytically activated during T cell activation. In Jurkat cells, furin is dispensable for immediate T cell receptor (TCR) signaling steps, such as ERK, ZAP70, or LAT phosphorylation. Furin regulates the expression of interleukin-2 in human Jurkat T cell lines, specific TGF-beta1-independent role for furin in interleukin-2 regulation. Furin activates specifically and nonredundantly the anti-inflammatory cytokine pro-TGF-beta1 and thus, directly modulates the activity of CD4+ and CD8+ T cells. Importantly, Furin regulates its own activity by autocleavage, and its mRNA and protein levels are modulated dynamically during alterations in T cell physiology. Furin does not affect TCR-induced immediate phosphorylation events in Jurkat T cells
physiological function
proprotein convertase substilisin/kexin-type (PCSK) enzymes regulate proprotein maturation by catalyzing the proteolytic cleavage of their substrates. The prototype PCSK furin is induced upon T-cell receptor (TCR) activation, and its expression in T cells is critical for the maintenance of peripheral immune tolerance. Proprotein convertase furin regulates T cell receptor-induced transactivation. TGF-beta1 and NOTCH1 are synthesized initially as inactive precursors and are proteolytically activated during T-cell activation. In Jurkat cells, furin is dispensable for immediate T-cell receptor (TCR) signaling steps, such as ERK, ZAP70, or LAT phosphorylation. Furin regulates the expression of interleukin-2 in human Jurkat T-cell lines, specific TGF-beta1-independent role for furin in interleukin-2 regulation. Furin activates specifically and nonredundantly the anti-inflammatory cytokine pro-TGF-beta1 and thus, directly modulates the activity of CD4+ and CD8+ T-cells. Importantly, Furin regulates its own activity by autocleavage, and its mRNA and protein levels are modulated dynamically during alterations in T-cell physiology
physiological function
proprotein convertases (PCs) are highly specific proteases required for the proteolytic modification of many secreted proteins. Calcium-dependent activity regulation of furin
physiological function
transforming growth factor beta (TGF-beta) is a signalling molecule that plays a key role in developmental and immunological processes in mammals. Pro-TGF-beta forms homodimers and is further processed in the trans-Golgi by a furin protease. Proteolytic cleavage by furin separates mature TGF-beta from latency-associated peptide (LAP). This dimeric complex is called the small latency complex (SLC) and keeps mature TGF-beta in an inactive form. Furin requires multiple processing steps and correct localization within the secretory pathway to become active
physiological function
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furin is upregulated and cleaves certain substrates during hypoxia in cancer cells, the enzyme mediates brain-derived neurotrophic factor upregulation in cultured rat astrocytes exposed to oxygen-glucose deprivation. Maturation of brain-derived neurotrophic factor in astrocytes requires furin-mediated endoproteolytic processing of the precursor protein pro-brain-derived neurotrophic factor to brain-derived neurotrophic factor
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additional information
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alpha1-PDX blocks cleavage of the S2 but not the S1 site of pro-BMP4 in embryos, suggesting the existence of a developmentally regulated S1 site-specific convertase, probably PC7, overview
additional information
enzyme modeling by molecular dynamics calculations. Furin shows a complex activation mechanism and exists in at least four defined states: (i) the off state, incompatible with substrate binding as seen in the unliganded enzyme; (ii) the active on state seen in inhibitor-bound furin; and the respective (iii) calcium-free and (iv) calcium-bound forms. The transition from the off to the on state is triggered by ligand binding at subsites S1 to S4 and appears to underlie the preferential recognition of the four-residue sequence motif of furin. Ligation by calcium at the PC-specific binding site II influences the active-site geometry and determines the rotamer state of the oxyanion hole-forming Asn295, and adds a second level of the activity modulation of furin. Analysis of substrate induced structural rearrangements of furin, the spatial restrictions at and around the catalytic serine residue 368 of furin are structurally reminiscent of typical trypsin-like proteases, overview. Hotspots of conformational changes include the catalytic residues His194, Ser368, Asn295 of the oxyanion hole, the sodium binding site (Thr309 and Ser316), and residues in direct contact with the inhibitor peptide (e.g. the region Ser253-Pro256, the alignment template). Mapping of the Calpha displacement to the surface of the structure induced by inhibitor binding reveals a concerted local rearrangement at the substrate-binding cleft
additional information
X-ray structures of the proprotein convertase furin bound with substrate analogue inhibitors reveal substrate specificity determinants beyond the S4 pocket, overview. Substrate specificity is mediated at the P4-P6 binding sites of furin