4OMC , 4OMD , 4RYD , 4Z2A
53-407: 5045 18550 ENSG00000140564 ENSMUSG00000030530 P09958 P23188 NM_002569 NM_001289823 NM_001289824 NM_001081454 NM_011046 NP_001369550 NP_001369551 NP_001276752.1 NP_001276753.1 NP_002560.1 NP_001074923 NP_035176 Furin is a protease , a proteolytic enzyme activated by substrate presentation that in humans and other animals
106-495: A Ayurvedic remedy for digestion and diabetes in the Indian subcontinent. It is also used to make Paneer . The activity of proteases is inhibited by protease inhibitors . One example of protease inhibitors is the serpin superfamily. It includes alpha 1-antitrypsin (which protects the body from excessive effects of its own inflammatory proteases), alpha 1-antichymotrypsin (which does likewise), C1-inhibitor (which protects
159-443: A peptide bond involves making an amino acid residue that has the cysteine and threonine (proteases) or a water molecule (aspartic, glutamic and metalloproteases) nucleophilic so that it can attack the peptide carbonyl group. One way to make a nucleophile is by a catalytic triad , where a histidine residue is used to activate serine , cysteine , or threonine as a nucleophile. This is not an evolutionary grouping, however, as
212-402: A multitude of physiological reactions from simple digestion of food proteins to highly regulated cascades (e.g., the blood-clotting cascade , the complement system , apoptosis pathways, and the invertebrate prophenoloxidase-activating cascade). Proteases can either break specific peptide bonds ( limited proteolysis ), depending on the amino acid sequence of a protein, or completely break down
265-437: A peptide to amino acids ( unlimited proteolysis ). The activity can be a destructive change (abolishing a protein's function or digesting it to its principal components), it can be an activation of a function, or it can be a signal in a signalling pathway. Plant genomes encode hundreds of proteases, largely of unknown function. Those with known function are largely involved in developmental regulation. Plant proteases also play
318-543: A role in cell regulation and differentiation. Lipophilic ligands, attached to lipocalin proteins, have been found to possess tumor protease inhibiting properties. The natural protease inhibitors are not to be confused with the protease inhibitors used in antiretroviral therapy. Some viruses , with HIV/AIDS among them, depend on proteases in their reproductive cycle. Thus, protease inhibitors are developed as antiviral therapeutic agents. Other natural protease inhibitors are used as defense mechanisms. Common examples are
371-441: A role in regulation of photosynthesis . Proteases are used throughout an organism for various metabolic processes. Acid proteases secreted into the stomach (such as pepsin ) and serine proteases present in the duodenum ( trypsin and chymotrypsin ) enable the digestion of protein in food. Proteases present in blood serum ( thrombin , plasmin , Hageman factor , etc.) play an important role in blood-clotting, as well as lysis of
424-542: A set of glycosylation enzymes that attach various sugar monomers to proteins as the proteins move through the apparatus. The Golgi apparatus was identified in 1898 by the Italian biologist and pathologist Camillo Golgi . The organelle was later named after him in the 1910s. Because of its large size and distinctive structure, the Golgi apparatus was one of the first organelles to be discovered and observed in detail. It
477-484: A stack; however, in some protists as many as sixty cisternae have been observed. This collection of cisternae is broken down into cis , medial, and trans compartments, making up two main networks: the cis Golgi network (CGN) and the trans Golgi network (TGN). The CGN is the first cisternal structure, and the TGN is the final, from which proteins are packaged into vesicles destined to lysosomes , secretory vesicles, or
530-764: Is a subtilisin -like peptidase. 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: pro parathyroid hormone , transforming growth factor beta 1 precursor, pro albumin , 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
583-469: Is a fungal metabolite used experimentally to disrupt the secretion pathway as a method of testing Golgi function. BFA blocks the activation of some ADP-ribosylation factors ( ARFs ). ARFs are small GTPases which regulate vesicular trafficking through the binding of COPs to endosomes and the Golgi. BFA inhibits the function of several guanine nucleotide exchange factors (GEFs) that mediate GTP-binding of ARFs. Treatment of cells with BFA thus disrupts
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#1732800792118636-616: Is achieved by proteases having a long binding cleft or tunnel with several pockets that bind to specified residues. For example, TEV protease is specific for the sequence ...ENLYFQ\S... ('\'=cleavage site). Proteases, being themselves proteins, are cleaved by other protease molecules, sometimes of the same variety. This acts as a method of regulation of protease activity. Some proteases are less active after autolysis (e.g. TEV protease ) whilst others are more active (e.g. trypsinogen ). Proteases occur in all organisms, from prokaryotes to eukaryotes to viruses . These enzymes are involved in
689-440: Is also involved in lipid transport and lysosome formation. The structure and function of the Golgi apparatus are intimately linked. Individual stacks have different assortments of enzymes, allowing for progressive processing of cargo proteins as they travel from the cisternae to the trans Golgi face. Enzymatic reactions within the Golgi stacks occur exclusively near its membrane surfaces, where enzymes are anchored. This feature
742-531: Is also thought to play a role in tumor progression. The use of alternate polyadenylation sites has been found for the FURIN gene. Furin is enriched in the Golgi apparatus , where it functions to cleave other proteins into their mature/active forms. 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
795-404: 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 , 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
848-552: 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. 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 ( P aired basic A mino acid C leaving E nzyme). A member of family S8 , furin
901-704: Is found in the MEROPS database. In this database, proteases are classified firstly by 'clan' ( superfamily ) based on structure, mechanism and catalytic residue order (e.g. the PA clan where P indicates a mixture of nucleophile families). Within each 'clan', proteases are classified into families based on sequence similarity (e.g. the S1 and C3 families within the PA clan). Each family may contain many hundreds of related proteases (e.g. trypsin , elastase , thrombin and streptogrisin within
954-530: Is in contrast to the ER, which has soluble proteins and enzymes in its lumen . Much of the enzymatic processing is post-translational modification of proteins. For example, phosphorylation of oligosaccharides on lysosomal proteins occurs in the early CGN. Cis cisterna are associated with the removal of mannose residues. Removal of mannose residues and addition of N-acetylglucosamine occur in medial cisternae. Addition of galactose and sialic acid occurs in
1007-576: Is low, furin traffics to the disordered region. 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 . Furin has been shown to interact with PACS1 . Protease A protease (also called a peptidase , proteinase , or proteolytic enzyme ) is an enzyme that catalyzes proteolysis , breaking down proteins into smaller polypeptides or single amino acids , and spurring
1060-508: Is one of the fastest "switching on" and "switching off" regulatory mechanisms in the physiology of an organism. By a complex cooperative action, proteases can catalyze cascade reactions, which result in rapid and efficient amplification of an organism's response to a physiological signal. Bacteria secrete proteases to hydrolyse the peptide bonds in proteins and therefore break the proteins down into their constituent amino acids . Bacterial and fungal proteases are particularly important to
1113-413: Is unusual since, rather than hydrolysis , it performs an elimination reaction . During this reaction, the catalytic asparagine forms a cyclic chemical structure that cleaves itself at asparagine residues in proteins under the right conditions. Given its fundamentally different mechanism, its inclusion as a peptidase may be debatable. An up-to-date classification of protease evolutionary superfamilies
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#17328007921181166-414: The Golgi , is an organelle found in most eukaryotic cells . Part of the endomembrane system in the cytoplasm , it packages proteins into membrane-bound vesicles inside the cell before the vesicles are sent to their destination. It resides at the intersection of the secretory, lysosomal, and endocytic pathways. It is of particular importance in processing proteins for secretion , containing
1219-438: The hepatitis C virus and the picornaviruses ). These proteases (e.g. TEV protease ) have high specificity and only cleave a very restricted set of substrate sequences. They are therefore a common target for protease inhibitors . Archaea use proteases to regulate various cellular processes from cell-signaling , metabolism , secretion and protein quality control. Only two ATP-dependent proteases are found in archaea:
1272-462: The spike protein into two portions (S1 and S2), which remain associated. 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. Furin is regulated by cholesterol and substrate presentation . When cholesterol is high, furin traffics to GM1 lipid rafts . When cholesterol
1325-485: The trans cisternae. Sulfation of tyrosines and carbohydrates occurs within the TGN. Other general post-translational modifications of proteins include the addition of carbohydrates ( glycosylation ) and phosphates ( phosphorylation ). Protein modifications may form a signal sequence that determines the final destination of the protein. For example, the Golgi apparatus adds a mannose-6-phosphate label to proteins destined for lysosomes. Another important function of
1378-429: The trans-Golgi network (TGN). This area of the Golgi is the point at which proteins are sorted and shipped to their intended destinations by their placement into one of at least three different types of vesicles, depending upon the signal sequence they carry. Though there are multiple models that attempt to explain vesicular traffic throughout the Golgi, no individual model can independently explain all observations of
1431-421: The trypsin inhibitors found in the seeds of some plants, most notable for humans being soybeans, a major food crop, where they act to discourage predators. Raw soybeans are toxic to many animals, including humans, until the protease inhibitors they contain have been denatured. Golgi apparatus The Golgi apparatus ( / ˈ ɡ ɒ l dʒ i / ), also known as the Golgi complex , Golgi body , or simply
1484-481: The AAA+ proteasome ) by degrading unfolded or misfolded proteins . A secreted bacterial protease may also act as an exotoxin, and be an example of a virulence factor in bacterial pathogenesis (for example, exfoliative toxin ). Bacterial exotoxic proteases destroy extracellular structures. The genomes of some viruses encode one massive polyprotein , which needs a protease to cleave this into functional units (e.g.
1537-406: The Golgi apparatus is in the formation of proteoglycans . Enzymes in the Golgi append proteins to glycosaminoglycans , thus creating proteoglycans. Glycosaminoglycans are long unbranched polysaccharide molecules present in the extracellular matrix of animals. The vesicles that leave the rough endoplasmic reticulum are transported to the cis face of the Golgi apparatus, where they fuse with
1590-399: The Golgi apparatus is made up of a series of compartments and is a collection of fused, flattened membrane-enclosed disks known as cisternae (singular: cisterna , also called "dictyosomes"), originating from vesicular clusters that bud off the endoplasmic reticulum (ER). A mammalian cell typically contains 40 to 100 stacks of cisternae. Between four and eight cisternae are usually present in
1643-461: The Golgi apparatus varies among eukaryotes. In mammals, a single Golgi apparatus is usually located near the cell nucleus, close to the centrosome. Tubular connections are responsible for linking the stacks together. Localization and tubular connections of the Golgi apparatus are dependent on microtubules . In experiments it is seen that as microtubules are depolymerized the Golgi apparatuses lose mutual connections and become individual stacks throughout
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1696-425: The Golgi apparatus. Currently, the cisternal progression/maturation model is the most accepted among scientists, accommodating many observations across eukaryotes. The other models are still important in framing questions and guiding future experimentation. Among the fundamental unanswered questions are the directionality of COPI vesicles and role of Rab GTPases in modulating protein cargo traffic. Brefeldin A (BFA)
1749-412: The Golgi membrane and empty their contents into the lumen . Once inside the lumen, the molecules are modified, then sorted for transport to their next destinations. Those proteins destined for areas of the cell other than either the endoplasmic reticulum or the Golgi apparatus are moved through the Golgi cisternae towards the trans face, to a complex network of membranes and associated vesicles known as
1802-407: The S1 family). Currently more than 50 clans are known, each indicating an independent evolutionary origin of proteolysis. Alternatively, proteases may be classified by the optimal pH in which they are active: Proteases are involved in digesting long protein chains into shorter fragments by splitting the peptide bonds that link amino acid residues. Some detach the terminal amino acids from
1855-563: The array of proteins ingested into smaller peptide fragments. Promiscuous proteases typically bind to a single amino acid on the substrate and so only have specificity for that residue. For example, trypsin is specific for the sequences ...K\... or ...R\... ('\'=cleavage site). Conversely some proteases are highly specific and only cleave substrates with a certain sequence. Blood clotting (such as thrombin ) and viral polyprotein processing (such as TEV protease ) requires this level of specificity in order to achieve precise cleavage events. This
1908-399: The body from excessive protease-triggered activation of its own complement system ), antithrombin (which protects the body from excessive coagulation ), plasminogen activator inhibitor-1 (which protects the body from inadequate coagulation by blocking protease-triggered fibrinolysis ), and neuroserpin . Natural protease inhibitors include the family of lipocalin proteins, which play
1961-409: The cell surface. The TGN is usually positioned adjacent to the stack, but can also be separate from it. The TGN may act as an early endosome in yeast and plants. There are structural and organizational differences in the Golgi apparatus among eukaryotes. In some yeasts, Golgi stacking is not observed. Pichia pastoris does have stacked Golgi, while Saccharomyces cerevisiae does not. In plants,
2014-448: The clots, and the correct action of the immune system. Other proteases are present in leukocytes ( elastase , cathepsin G ) and play several different roles in metabolic control. Some snake venoms are also proteases, such as pit viper haemotoxin and interfere with the victim's blood clotting cascade. Proteases determine the lifetime of other proteins playing important physiological roles like hormones, antibodies, or other enzymes. This
2067-511: The cytoplasm. In yeast , multiple Golgi apparatuses are scattered throughout the cytoplasm (as observed in Saccharomyces cerevisiae ). In plants , Golgi stacks are not concentrated at the centrosomal region and do not form Golgi ribbons. Organization of the plant Golgi depends on actin cables and not microtubules. The common feature among Golgi is that they are adjacent to endoplasmic reticulum (ER) exit sites. In most eukaryotes,
2120-490: The development of modern microscopes in the twentieth century, the discovery was confirmed. Early references to the Golgi apparatus referred to it by various names, including the Golgi–Holmgren apparatus, Golgi–Holmgren ducts, and Golgi–Kopsch apparatus. The term Golgi apparatus was used in 1910 and first appeared in scientific literature in 1913, while "Golgi complex" was introduced in 1956. The subcellular localization of
2173-437: The endoplasmic reticulum. Proteins synthesized in the ER are packaged into vesicles, which then fuse with the Golgi apparatus. These cargo proteins are modified and destined for secretion via exocytosis or for use in the cell. In this respect, the Golgi can be thought of as similar to a post office: it packages and labels items which it then sends to different parts of the cell or to the extracellular space . The Golgi apparatus
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2226-458: The fate of the protein. The compartmentalization of the Golgi apparatus is advantageous for separating enzymes, thereby maintaining consecutive and selective processing steps: enzymes catalyzing early modifications are gathered in the cis face cisternae, and enzymes catalyzing later modifications are found in trans face cisternae of the Golgi stacks. The Golgi apparatus is a major collection and dispatch station of protein products received from
2279-592: The formation of new protein products. They do this by cleaving the peptide bonds within proteins by hydrolysis , a reaction where water breaks bonds . Proteases are involved in numerous biological pathways, including digestion of ingested proteins, protein catabolism (breakdown of old proteins), and cell signaling . In the absence of functional accelerants, proteolysis would be very slow, taking hundreds of years . Proteases can be found in all forms of life and viruses . They have independently evolved multiple times , and different classes of protease can perform
2332-489: The global carbon and nitrogen cycles in the recycling of proteins, and such activity tends to be regulated by nutritional signals in these organisms. The net impact of nutritional regulation of protease activity among the thousands of species present in soil can be observed at the overall microbial community level as proteins are broken down in response to carbon, nitrogen, or sulfur limitation. Bacteria contain proteases responsible for general protein quality control (e.g.
2385-606: The individual stacks of the Golgi apparatus seem to operate independently. The Golgi apparatus tends to be larger and more numerous in cells that synthesize and secrete large amounts of substances; for example, the antibody -secreting plasma B cells of the immune system have prominent Golgi complexes. In all eukaryotes, each cisternal stack has a cis entry face and a trans exit face. These faces are characterized by unique morphology and biochemistry . Within individual stacks are assortments of enzymes responsible for selectively modifying protein cargo. These modifications influence
2438-591: The membrane associated LonB protease and a soluble 20S proteosome complex . The field of protease research is enormous. Since 2004, approximately 8000 papers related to this field were published each year. Proteases are used in industry, medicine and as a basic biological research tool. Digestive proteases are part of many laundry detergents and are also used extensively in the bread industry in bread improver . A variety of proteases are used medically both for their native function (e.g. controlling blood clotting) or for completely artificial functions ( e.g. for
2491-446: The nucleophile types have evolved convergently in different superfamilies , and some superfamilies show divergent evolution to multiple different nucleophiles. Metalloproteases, aspartic, and glutamic proteases utilize their active site residues to activate a water molecule, which then attacks the scissile bond. A seventh catalytic type of proteolytic enzymes, asparagine peptide lyase , was described in 2011. Its proteolytic mechanism
2544-460: 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
2597-467: The protein chain ( exopeptidases , such as aminopeptidases , carboxypeptidase A ); others attack internal peptide bonds of a protein ( endopeptidases , such as trypsin , chymotrypsin , pepsin , papain , elastase ). Catalysis is achieved by one of two mechanisms: Proteolysis can be highly promiscuous such that a wide range of protein substrates are hydrolyzed. This is the case for digestive enzymes such as trypsin , which have to be able to cleave
2650-449: The same reaction by completely different catalytic mechanisms . Proteases can be classified into seven broad groups: Proteases were first grouped into 84 families according to their evolutionary relationship in 1993, and classified under four catalytic types: serine , cysteine , aspartic , and metallo proteases. The threonine and glutamic proteases were not described until 1995 and 2004 respectively. The mechanism used to cleave
2703-424: The soluble forms of HJV/hemojuvelin (s-hemojuvelin) found in the blood of rodents and humans. The furin substrates and the locations of furin cleavage sites in protein sequences can be predicted by two bioinformatics methods: ProP and PiTou. 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. This protease
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#17328007921182756-580: The targeted degradation of pathogenic proteins). Highly specific proteases such as TEV protease and thrombin are commonly used to cleave fusion proteins and affinity tags in a controlled fashion. Protease-containing plant-solutions called vegetarian rennet have been in use for hundreds of years in Europe and the Middle East for making kosher and halal Cheeses . Vegetarian rennet from Withania coagulans has been in use for thousands of years as
2809-408: Was discovered in 1898 by Italian physician Camillo Golgi during an investigation of the nervous system . After first observing it under his microscope , he termed the structure as apparato reticolare interno ("internal reticular apparatus"). Some doubted the discovery at first, arguing that the appearance of the structure was merely an optical illusion created by Golgi’s observation technique. With
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