Complement component 1q
The complement component 1q is a protein complex involved in the complement system, part of the innate immune system. C1q together with C1s form the C1 complex. Antibodies of the adaptive immune system can bind antigen; when C1q binds antigen-antibody complexes, the C1 complex becomes activated. Activation of the C1 complex initiates the classical complement pathway of the complement system; the antibodies IgM and all IgG subclasses. C1q is a 400 kDa protein formed from 18 peptide chains in 3 subunits of 6; each 6 peptide subunit consists of a Y-shaped pair of triple peptide helices joined at the stem and ending in a globular non-helical head. The 80-amino acid helical component of each triple peptide contain many Gly-X-Y sequences, where X and Y are proline, isoleucine, or hydroxylysine. C1q is composed of 18 polypeptide chains: six A-chains, six B-chains, six C-chains; each chain contains a collagen-like region located near the N terminus and a C-terminal globular region. The A-, B-, C-chains are arranged in the order A-C-B on chromosome 1.
The C1q domain is a conserved protein domain. C1q is a subunit of the C1 enzyme complex. C1q comprises 6 B and 6 C chains; these share the same topology, each possessing a small, globular N-terminal domain, a collagen-like Gly/Pro-rich central region, a conserved C-terminal region, the C1q domain. The C1q protein is produced in collagen-producing cells and shows sequence and structural similarity to collagens VIII and X, it is assumed that the globular ends are the sites for multivalent attachment to the complement fixing sites in immune complexed immunoglobulin. Patients suffering from Lupus erythematosus have deficient expression of C1q. Genetic deficiency of C1q is rare although the majority of those suffer from SLE. C1q may play a central role in the aging of cells. C1q associates with C1r and C1s in order to yield the C1 complex, the first component of the serum complement system. Deficiency of C1q has been associated with lupus glomerulonephritis, it is multivalent for attachment to the complement fixation sites of immunoglobulin.
The sites are on the CH2 domain of IgG and, it is thought, on the CH4 domain of IgM. IgG4 can not bind C1q; the appropriate peptide sequence of the complement fixing site might become exposed following complexing of the immunoglobulin, or the sites might always be available, but might require multiple attachment by C1q with critical geometry in order to achieve the necessary avidity. C1q: structure and receptors. Kishore U1, Reid KB. Immunopharmacology. 2000 Aug. Functional Complement C1q Abnormality Leads to Impaired Immune Complexes and Apoptotic Cell Clearance. Deciphering the fine details of C1 assembly and activation mechanisms: “mission impossible”? - detailed diagrams Complement+C1q at the US National Library of Medicine Medical Subject Headings
International Standard Serial Number
An International Standard Serial Number is an eight-digit serial number used to uniquely identify a serial publication, such as a magazine. The ISSN is helpful in distinguishing between serials with the same title. ISSN are used in ordering, interlibrary loans, other practices in connection with serial literature; the ISSN system was first drafted as an International Organization for Standardization international standard in 1971 and published as ISO 3297 in 1975. ISO subcommittee TC 46/SC 9 is responsible for maintaining the standard; when a serial with the same content is published in more than one media type, a different ISSN is assigned to each media type. For example, many serials are published both in electronic media; the ISSN system refers to these types as electronic ISSN, respectively. Conversely, as defined in ISO 3297:2007, every serial in the ISSN system is assigned a linking ISSN the same as the ISSN assigned to the serial in its first published medium, which links together all ISSNs assigned to the serial in every medium.
The format of the ISSN is an eight digit code, divided by a hyphen into two four-digit numbers. As an integer number, it can be represented by the first seven digits; the last code digit, which may be 0-9 or an X, is a check digit. Formally, the general form of the ISSN code can be expressed as follows: NNNN-NNNC where N is in the set, a digit character, C is in; the ISSN of the journal Hearing Research, for example, is 0378-5955, where the final 5 is the check digit, C=5. To calculate the check digit, the following algorithm may be used: Calculate the sum of the first seven digits of the ISSN multiplied by its position in the number, counting from the right—that is, 8, 7, 6, 5, 4, 3, 2, respectively: 0 ⋅ 8 + 3 ⋅ 7 + 7 ⋅ 6 + 8 ⋅ 5 + 5 ⋅ 4 + 9 ⋅ 3 + 5 ⋅ 2 = 0 + 21 + 42 + 40 + 20 + 27 + 10 = 160 The modulus 11 of this sum is calculated. For calculations, an upper case X in the check digit position indicates a check digit of 10. To confirm the check digit, calculate the sum of all eight digits of the ISSN multiplied by its position in the number, counting from the right.
The modulus 11 of the sum must be 0. There is an online ISSN checker. ISSN codes are assigned by a network of ISSN National Centres located at national libraries and coordinated by the ISSN International Centre based in Paris; the International Centre is an intergovernmental organization created in 1974 through an agreement between UNESCO and the French government. The International Centre maintains a database of all ISSNs assigned worldwide, the ISDS Register otherwise known as the ISSN Register. At the end of 2016, the ISSN Register contained records for 1,943,572 items. ISSN and ISBN codes are similar in concept. An ISBN might be assigned for particular issues of a serial, in addition to the ISSN code for the serial as a whole. An ISSN, unlike the ISBN code, is an anonymous identifier associated with a serial title, containing no information as to the publisher or its location. For this reason a new ISSN is assigned to a serial each time it undergoes a major title change. Since the ISSN applies to an entire serial a new identifier, the Serial Item and Contribution Identifier, was built on top of it to allow references to specific volumes, articles, or other identifiable components.
Separate ISSNs are needed for serials in different media. Thus, the print and electronic media versions of a serial need separate ISSNs. A CD-ROM version and a web version of a serial require different ISSNs since two different media are involved. However, the same ISSN can be used for different file formats of the same online serial; this "media-oriented identification" of serials made sense in the 1970s. In the 1990s and onward, with personal computers, better screens, the Web, it makes sense to consider only content, independent of media; this "content-oriented identification" of serials was a repressed demand during a decade, but no ISSN update or initiative occurred. A natural extension for ISSN, the unique-identification of the articles in the serials, was the main demand application. An alternative serials' contents model arrived with the indecs Content Model and its application, the digital object identifier, as ISSN-independent initiative, consolidated in the 2000s. Only in 2007, ISSN-L was defined in the
Complement membrane attack complex
The membrane attack complex or terminal complement complex is a structure formed on the surface of pathogen cell membranes as a result of the activation of the host's complement system, as such is one of the effector proteins of the immune system. The membrane-attack complex forms transmembrane channels; these channels disrupt the cell membrane of target cells, leading to death. Active MAC is composed of the subunits C5b, C7, C8 and several C9 molecules. A number of proteins participate in the assembly of the MAC. Freshly activated C5b binds to C6 to form a C5b-6 complex to C7 forming the C5b-6-7 complex; the C5b-6-7 complex binds to C8, composed of three chains, thus forming the C5b-6-7-8 complex. C5b-6-7-8 subsequently binds to C9 and acts as a catalyst in the polymerization of C9. MAC is composed of a complex of four complement proteins that bind to the outer surface of the plasma membrane, many copies of a fifth protein that hook up to one another, forming a ring in the membrane. C6-C9 all contain a common MACPF domain.
This region is homologous to cholesterol-dependent cytolysins from Gram-positive bacteria. The ring structure formed by C9 is a pore in the membrane that allows free diffusion of molecules in and out of the cell. If enough pores form, the cell is no longer able to survive. If the pre-MAC complexes of C5b-7, C5b-8 or C5b-9 do not insert into a membrane, they can form inactive complexes with Protein S; these fluid phase complexes do not bind to cell membranes and are scavenged by clusterin and vitronectin, two regulators of complement. The membrane attack complex is initiated when the complement protein C5 convertase cleaves C5 into C5a and C5b. All three pathways of the complement system initiate the formation of MAC. Another complement protein, C6, binds to C5b; the C5bC6 complex is bound by C7. This junction alters the configuration of the protein molecules exposing a hydrophobic site on C7 that allows the C7 to insert into the phospholipid bilayer of the pathogen. Similar hydrophobic sites on C8 and C9 molecules are exposed when they bind to the complex, so they can insert into the bilayer.
C8 is a complex made of C8 alpha-gamma. C8 alpha-gamma has the hydrophobic area. C8 alpha-gamma induces the polymerization of 10-16 molecules of C9 into a pore-forming structure known as the membrane attack complex. MAC has a hydrophobic external face allowing it to associate with the lipid bilayer. MAC has a hydrophilic internal face to allow the passage of water. Multiple molecules of C9 can join spontaneously in concentrated solution to form polymers of C9; these polymers can form a tube-like structure. CD59 acts to inhibit the complex; this exists on body cells to protect them from MAC. A rare condition, paroxysmal nocturnal haemoglobinuria, results in red blood cells that lack CD59; these cells can, therefore, be lysed by MAC. Deficiencies of C5 to C9 components does not lead to generic infections, but only to increased susceptibility to Neisseria spp. since these bacteria have a thick cell wall and glycocalix. Terminal complement pathway deficiency Perforin Pore-forming toxin Media related to Complement membrane attack complex at Wikimedia Commons Complement+Membrane+Attack+Complex at the US National Library of Medicine Medical Subject Headings
C5 convertase is an enzyme belonging to a family of serine proteases that play key role in the innate immunity. It participates in the complement system ending with cell death. There are four different C5 convertases able to convert the protein C5 to C5a and C5b fragments. Two of the convertases are physiological complement enzymes, associate to the cell-surface and mediate the classical pathway or the alternative pathway of complement system. Two fluid phase C5 convertases have been described: the classical pathway enzyme, C4b2boxy3b and the cobra venom factor-dependent C5 convertase, CVFBb. Cell-bound C3 and C5 convertase differ in their C3b requirement. C3-convertase need only one molecule of C3b to form, whereas two or more C3b are required for generation of C5 convertase, it means, when C3b is randomly distributed on the surface of a cell, only C3 convertase activity appears after addition of Factors B and D. However, when C3b is distributed in clusters, C3 and C5 convertase activity is generated upon addition of Factors B and D.
The classical pathway C5 convertase is composed of the larger fragments of complement proteins, C4b, C2b produced by cleavage mediated by C1 complex, C3b produced by cleavage mediated by the classical pathway C3 convertase. The formation of the alternative pathway C5 convertase starts by spontaneous cleavage of C3 protein exposing hidden thioester bond. In the presence of pathogen the fragment C3b binds to microbial cell-surface through the newly showed thioester bond. On the other hand, if the infection does not occur, C3b interacts with molecules of water, therefore the protein becomes inactive. However, when C3b undergoes its post-cleveage conformational change, a binding site for a plasma protein called Factor B is exposed. Factor B binds to C3b and is cleaved by a plasma serine protease Factor D; the C3bBb complex remains attached to the cell-surface. This complex might thus form the alternative pathway C5 convertase. CVFBb is a noncovalent association product of the complement fragment Bb.
The catalytic subunits of these multimolecular proteases are Bb. These subunits belong to atypical serine proteases. CVFBb does not require C3 for cleavage of C5, whereas C4b2boxy need native C3 for cleavage of C5 protein; the modified C5 convertase, C4b2boxy3b, contains C2b, derived from C2 oxidized by iodine. The target of C5 convertase is complement protein C5. C5 is a two-chain plasma glycoprotein. C5 and C3 have similar structure. However, C5 does not appear to contain the internal thiol ester group reported for C3 and C4. C5 has few disulfide bonds. There are three disulfide bonds in C5a, the α-chain has 15 half-Cystines, the β-chain has only 6 half-Cystines; this comparatively low level of stabilizing disulfide bridges may provide a partial explanation for the irreversible conformational change imparted on C5 after cleavage to C5a and C5b. In addition, the low number of disulfide bonds could account for instability of C5 when exposed to chaotropic agents such as potassium thiocyanate. Electron micrographs of negatively stained C5 indicate that the protein is irregular in shape and contains several lobes.
First of all, C5 has to bind to C3b fragment. The capacity to bind C3b is a stable feature of component C5, as C5b has this binding capacity; the C5 convertase selectively cleaves an Arginyl-Leucine peptide bond at position 74-75 in the α-chain of C5. Α' - chain and the activation peptide, C5a, is formed. The complement component C5 can be activated by fluid phase C5 convertase. C5 is activated by CVFBb in the presence of complement component C6 and the C5b6 complex is formed. However, when C6 is added after C5 has been converted to C5b, the C5b6 complex fails to form. Therefore, the activation of C5 results in a transient binding site for C6. Hydrophobic sites are exposed upon C5 activation because C5b undergoes aggregation when C5 is converted to C5b in the absence of C6. Interactions between C5 and C6 or C5 and membranes are noncovalent; the proteolytic cleavage of C5 is the only known enzymatic event in assembly of the cytolytic membrane attack complex of complement. Once bound, C5 is exceptionally efficient in producing hemolysis, requiring less than seven bound molecules per cell for the production of a hemolytic lesion.
The extent of formation of the C5 intermediate complex is dependent on the number of molecules of C4, C2 and C3 present on the cells employed for its generation. In these respects, the mode of action of C5 is analogous to that of the other components of complement; the C5 step differs, however, in other aspects. The binding of C5 is influenced by C6 and C7, components which are thought to act subsequent to it in the complement sequence. In addition, the hemolytic activity of the isolated C5 intermediate complex is exceedingly labile, having an average half-life at 30 °C of only 9 rain; this characteristic distinguishes the C5 step, along with the C2 step, as rate-limiting in the complement reaction. However, unlike C2, C5 remains cell-bound during the decay process and undergoes an alteration in situ which renders it hemolytically unreactive. C5 is unique in that it adsorbs in native form to unsensitized erythrocytes; this nonspecifically bound C5 remains attached, although it may be utilized as a source of C5 by an ongoing complement reaction.
Both enzymes, C4b2b3b and C3
Anaphylatoxins, or complement peptides, are fragments that are produced as part of the activation of the complement system. Complement components C3, C4 and C5 are large glycoproteins that have important functions in the immune response and host defense, they have a wide variety of biological activities and are proteolytically activated by cleavage at a specific site, forming a- and b-fragments. A-fragments form distinct structural domains of 76 amino acids, coded for by a single exon within the complement protein gene; the C3a, C4a and C5a components are referred to as anaphylatoxins: they cause smooth muscle contraction, histamine release from mast cells, enhanced vascular permeability. They mediate chemotaxis and generation of cytotoxic oxygen radicals; the proteins are hydrophilic, with a alpha-helical structure held together by 3 disulfide bridges. Anaphylatoxins are able to trigger degranulation of endothelial cells, mast cells or phagocytes, which produce a local inflammatory response.
If the degranulation is widespread, it can cause a shock-like syndrome similar to that of an allergic reaction. Anaphylatoxins indirectly mediate: smooth muscle cells contraction, for example bronchospasms increase in the permeability of blood capillaries C5a indirectly mediates chemotaxis — receptor-mediated movement of leukocytes in the direction of the increasing concentration of anaphylatoxins Important anaphylatoxins: C5a has the highest specific biological activity and is able to act directly on neutrophils and monocytes to speed up the phagocytosis of pathogens. C3a works with C5a to activate mast cells, recruit antibody and phagocytic cells and increase fluid in the tissue, all of which contribute to the initiation of the adaptive immune response. C4a is the least active anaphylatoxin. Although some drugs and some neurotransmitters are important mediators of degranulation of mast cells or basophils, they are not called anaphylatoxins; this term is reserved only for fragments of the complement system.
C3, C4A, C4B, C4B-1, C5, FBLN1, FBLN2 Anaphylatoxin at the US National Library of Medicine Medical Subject Headings
Immunoglobulin G is a type of antibody. Representing 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are released by plasma B cells; each IgG has two antigen binding sites. Antibodies are major components of humoral immunity. IgG is the main type of antibody found in blood and extracellular fluid, allowing it to control infection of body tissues. By binding many kinds of pathogens such as viruses and fungi, IgG protects the body from infection, it does this through several mechanisms: IgG-mediated binding of pathogens causes their immobilization and binding together via agglutination. IgG antibodies are generated following class switching and maturation of the antibody response, thus they participate predominantly in the secondary immune response. IgG is secreted as a monomer, small in size allowing it to perfuse tissues, it is the only antibody isotype that has receptors to facilitate passage through the human placenta, thereby providing protection to the fetus in utero.
Along with IgA secreted in the breast milk, residual IgG absorbed through the placenta provides the neonate with humoral immunity before its own immune system develops. Colostrum contains a high percentage of IgG bovine colostrum. In individuals with prior immunity to a pathogen, IgG appears about 24–48 hours after antigenic stimulation. Therefore, in the first six months of life, the newborn has the same antibodies as the mother and the child can defend itself against all the pathogens that the mother encountered in her life until these antibodies are degraded; this repertoire of immunoglobulins is crucial for the newborns who are sensitive to infections above all for the respiratory and digestive systems. IgG are involved in the regulation of allergic reactions. According to Finkelman, there are two pathways of systemic anaphylaxis: antigens can cause systemic anaphylaxis in mice through classic pathway by cross-linking IgE bound to the mast cell receptor FcεRI, stimulating the release of both histamine and platelet activating factor.
In the alternative pathway antigens form complexes with IgG, which cross-link macrophage receptor FcγRIII and stimulates only PAF release. IgG antibodies can prevent IgE mediated anaphylaxis by intercepting a specific antigen before it binds to mast cell–associated IgE. IgG antibodies block systemic anaphylaxis induced by small quantities of antigen but can mediate systemic anaphylaxis induced by larger quantities. IgG antibodies are large molecules with a molecular weight of about 150 kDa made of four peptide chains, it contains two identical class γ heavy chains of about 50 kDa and two identical light chains of about 25 kDa, thus a tetrameric quaternary structure. The two heavy chains are linked to a light chain each by disulfide bonds; the resulting tetramer has two identical halves. Each end of the fork contains an identical antigen binding site; the various regions and domains of a typical IgG are depicted in the figure to the left. The Fc regions of IgGs bear a conserved N-glycosylation site.
The N-glycans attached to this site are predominantly core-fucosylated diantennary structures of the complex type. In addition, small amounts of these N-glycans bear bisecting GlcNAc and α-2,6-linked sialic acid residues. There are four IgG subclasses in humans, named in order of their abundance in serum. Note: IgG affinity to Fc receptors on phagocytic cells is specific to individual species from which the antibody comes as well as the class; the structure of the hinge regions contributes to the unique biological properties of each of the four IgG classes. Though there is about 95% similarity between their Fc regions, the structure of the hinge regions is different. Given the opposing properties of the IgG subclasses, the fact that the immune response to most antigens includes a mix of all four subclasses, it has been difficult to understand how IgG subclasses can work together to provide protective immunity; the Temporal Model of human IgE and IgG function was proposed. This model suggests; the IgG3, though of low affinity, allows IgG-mediated defences to join IgM-mediated defences in clearing foreign antigens.
Subsequently, higher affinity IgG1 and IgG2 are produced. The relative balance of these subclasses, in any immune complexes that form, helps determine the strength of the inflammatory processes that follow. If antigen persists, high affinity IgG4 is produced, which dampens down inflammation by helping to curtail FcR-mediated processes; the relative ability of different IgG subclasses to fix complement may explain why some anti-donor antibody responses do harm a graft after organ transplantation. In a mouse model of autoantibody mediated anemia using IgG isotype swit
Proteins are large biomolecules, or macromolecules, consisting of one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, responding to stimuli, providing structure to cells and organisms, transporting molecules from one location to another. Proteins differ from one another in their sequence of amino acids, dictated by the nucleotide sequence of their genes, which results in protein folding into a specific three-dimensional structure that determines its activity. A linear chain of amino acid residues is called a polypeptide. A protein contains at least one long polypeptide. Short polypeptides, containing less than 20–30 residues, are considered to be proteins and are called peptides, or sometimes oligopeptides; the individual amino acid residues are bonded together by peptide bonds and adjacent amino acid residues. The sequence of amino acid residues in a protein is defined by the sequence of a gene, encoded in the genetic code.
In general, the genetic code specifies 20 standard amino acids. Shortly after or during synthesis, the residues in a protein are chemically modified by post-translational modification, which alters the physical and chemical properties, stability and the function of the proteins. Sometimes proteins have non-peptide groups attached, which can be called prosthetic groups or cofactors. Proteins can work together to achieve a particular function, they associate to form stable protein complexes. Once formed, proteins only exist for a certain period and are degraded and recycled by the cell's machinery through the process of protein turnover. A protein's lifespan covers a wide range, they can exist for years with an average lifespan of 1 -- 2 days in mammalian cells. Abnormal or misfolded proteins are degraded more either due to being targeted for destruction or due to being unstable. Like other biological macromolecules such as polysaccharides and nucleic acids, proteins are essential parts of organisms and participate in every process within cells.
Many proteins are enzymes that are vital to metabolism. Proteins have structural or mechanical functions, such as actin and myosin in muscle and the proteins in the cytoskeleton, which form a system of scaffolding that maintains cell shape. Other proteins are important in cell signaling, immune responses, cell adhesion, the cell cycle. In animals, proteins are needed in the diet to provide the essential amino acids that cannot be synthesized. Digestion breaks the proteins down for use in the metabolism. Proteins may be purified from other cellular components using a variety of techniques such as ultracentrifugation, precipitation and chromatography. Methods used to study protein structure and function include immunohistochemistry, site-directed mutagenesis, X-ray crystallography, nuclear magnetic resonance and mass spectrometry. Most proteins consist of linear polymers built from series of up to 20 different L-α- amino acids. All proteinogenic amino acids possess common structural features, including an α-carbon to which an amino group, a carboxyl group, a variable side chain are bonded.
Only proline differs from this basic structure as it contains an unusual ring to the N-end amine group, which forces the CO–NH amide moiety into a fixed conformation. The side chains of the standard amino acids, detailed in the list of standard amino acids, have a great variety of chemical structures and properties; the amino acids in a polypeptide chain are linked by peptide bonds. Once linked in the protein chain, an individual amino acid is called a residue, the linked series of carbon and oxygen atoms are known as the main chain or protein backbone; the peptide bond has two resonance forms that contribute some double-bond character and inhibit rotation around its axis, so that the alpha carbons are coplanar. The other two dihedral angles in the peptide bond determine the local shape assumed by the protein backbone; the end with a free amino group is known as the N-terminus or amino terminus, whereas the end of the protein with a free carboxyl group is known as the C-terminus or carboxy terminus.
The words protein and peptide are a little ambiguous and can overlap in meaning. Protein is used to refer to the complete biological molecule in a stable conformation, whereas peptide is reserved for a short amino acid oligomers lacking a stable three-dimensional structure. However, the boundary between the two is not well defined and lies near 20–30 residues. Polypeptide can refer to any single linear chain of amino acids regardless of length, but implies an absence of a defined conformation. Proteins can interact with many types of molecules, including with other proteins, with lipids, with carboyhydrates, with DNA, it has been estimated. Smaller bacteria, such as Mycoplasma or spirochetes contain fewer molecules, on the order of 50,000 to 1 million. By contrast, eukaryotic cells are larger and thus contain much more pro