Constituent of the membrane attack complex (MAC) that plays a key role in the innate and adaptive immune response by forming pores in the plasma membrane of target cells. C8A inserts into the target membrane, but does not form pores by itself.
Membrane attack is important for mammalian immune defense against invading microorganisms and infected host cells. Proteins of the complement membrane attack complex (MAC) and the protein perforin share a common MACPF domain that is responsible for membrane insertion and pore formation. We determined the crystal structure of the MACPF domain of complement component C8alpha at 2.5 angstrom resolution and show that it is structurally homologous to the bacterial, pore-forming, cholesterol-dependent cytolysins. The structure displays two regions that (in the bacterial cytolysins) refold into transmembrane beta hairpins, forming the lining of a barrel pore. Local hydrophobicity explains why C8alpha is the first complement protein to insert into the membrane. The size of the MACPF domain is consistent with known C9 pore sizes. These data imply that these mammalian and bacterial cytolytic proteins share a common mechanism of membrane insertion.
J. Biol. Chem. 255, 11997-12005 (1980)[PubMed:7440581]
The eighth component of human complement (C8) has been purified in high yield from Cohn Fraction III and characterized with regard to its physicochemical properties and subunit structure. The purified product was found to be similar to functional C8 isolated from plasma or serum. Human C8 possesses a molecular weight of 151,000 and is composed of a 1:1:1 ratio of three nonidentical subunits: alpha (Mr = 64,000), beta (Mr = 64,000), and gamma (Mr = 22,000). These subunits occur as a covalently linked alpha-gamma dimer which is noncovalently associated with beta. After purification and characterization of alpha, beta, and gamma, each was found to possess different amino acid compositions and NH2-terminal sequences. Both alpha and beta subunits contain similar but exceptionally high percentages of hydrophobic aromatic amino acids. As measured by circular dichroism, the secondary structure of C8 contains 12% alpha-helix, 24% beta structure, and 64% unordered structure, values typical of globular proteins. Complete secondary structure, as well as hemolytic activity, can be recovered after exposure to 6 M guanidinium hydrochloride or 8 M urea. The alpha-gamma and beta subunits were dissociated and isolated in the presence of sodium dodecyl sulfate and after removal of detergent, neither was found to possess independent hemolytic activity. Significantly, activity equivalent to that of native C8 was generated when alpha-gamma and beta were recombined in an equimolar ratio. These results indicate that C8 is an atypical serum protein with regard to both its subunit structure and denaturation characteristics.
Any process involved in the activation of any of the steps of the complement cascade, which allows for the direct killing of microbes, the disposal of immune complexes, and the regulation of other immune processes; the initial steps of complement activation involve one of three pathways, the classical pathway, the alternative pathway, and the lectin pathway, all of which lead to the terminal complement pathway.
Human C8 is one of five complement components (C5b, C6, C7, C8 and C9) that interact to form the cytolytic membrane attack complex (MAC) on bacterial cell membranes. It is an oligomeric protein composed of a disulfide-linked C8 alpha-gamma heterodimer and a non-covalently associated C8 beta chain. Previous studies revealed that C8 alpha and C8 beta have distinct roles in the formation of the MAC on simple cells such as erythrocytes and that both subunits are essential for cell lysis. These studies also determined that C8 gamma is not required for expression of MAC hemolytic activity. To determine if these conclusions are applicable to more biologically relevant systems, the C8 subunits were examined for their ability to support complement-mediated killing of Gram-negative bacteria. Results indicate: (1) C8 alpha-gamma, C8 alpha, C8 beta and C8 gamma have no independent bactericidal activity; (2) bacterial killing requires C8 beta and either C8 alpha-gamma or C8 alpha; (3) C8 alpha is an effective substitute for C8 alpha-gamma in bacterial killing; and (4) C8 gamma enhances, but is not required for C8 bactericidal activity. Together, these data suggest that C8 alpha and C8 beta have correspondingly similar roles in MAC-mediated lysis of erythrocytes and bacterial killing. Furthermore, they provide the first direct evidence that C8 gamma is not required for complement-mediated killing of Gram-negative bacteria.
Any process involved in the activation of any of the steps of the alternative pathway of the complement cascade which allows for the direct killing of microbes and the regulation of other immune processes.
Any process involved in the activation of any of the steps of the classical pathway of the complement cascade which allows for the direct killing of microbes, the disposal of immune complexes, and the regulation of other immune processes.
A patient is described who had a functional deficiency of the C8 complement component. His serum contained abnormal C8 which lacked some of the antigenic determinants of normal C8. The defect was associated with recurrent meningococcal infections due at different times to at least two strains. The patient's serum contained antibodies to meningococci and could induce phagocytosis and intracellular killing of the cocci by polymorphs. However, the serum was bactericidal only after the addition of C8-containing serum. As the patient did not give a history of susceptibility to other pyogenic organisms and has normal polymorph function, the circumstances of meningococcal infection must be unusual in that the plasma bactericidal activity critically determines the outcome: it may be that if large numbers of meningococci are not killed in the plasma, the polymorphs are overwhelmed.
Protein involved in the complement alternate pathway which activates the proteins of the complement system. This pathway can be activated by IgA immune complexes, but also by bacterial endotoxins, polysaccharides and cell walls, without participation of an antigen- antibody reaction.
Pathway which activates the proteins of the complement system, a group of blood proteins of the globulin class involved in the lysis of foreign cells after they have been coated with antibody, and which also promote the removal of antibody-coated foreign particles by phagocytic cells. The pathway proceeds by a cascade reaction of successive binding and proteolytic cleavage of complement components. This pathway can be activated by either IgG or IgM binding to an antigen.
Protein involved in immunity, any immune system process that functions in the response of an organism to a potential internal or invasive threat. The vertebrate immune system is formed by the innate immune system (composed of phagocytes, complement, antimicrobial peptides, etc) and by the adaptive immune system which consists of T- and B- lymphocytes.
Protein involved in innate immunity, an inborn defense mechanism used by organisms to defend themselves against invasion by pathogens (bacteria, fungi, viruses, etc.). Initially discovered in insects which are devoid of an adaptive immune system and rely only on innate immune reactions for their defense, this immediate response accomplishes many activities including recognition and effector functions. Recognition is mediated by broad specificity, pattern recognition, receptors which recognize many related molecular structures (e.g. polysaccharides, polynucleotides) present in microorganisms but not found in the host. The innate responses include the release of antimicrobial peptides, production of cytokines, acute- phase proteins, complement. Although many different innate immune mechanisms are deployed for host defence, a unifying theme of innate immunity is the use of germline-encoded pattern recognition receptors for pathogens or damaged self components, such as the Toll-like receptors, nucleotide-binding domain leucine-rich repeat (LRR)- containing receptors, retinoic acid-inducible gene I-like RNA helicases and C-type lectin receptors.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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