Complement component 4
Complement component 4 (C4) is a central protein in the complement system, specifically involved in the classical and lectin pathways of complement activation.
Upon activation by serine proteases (C1s in the classical pathway or MASP-2 in the lectin pathway), C4 is cleaved into C4a and C4b.
The C4b fragment covalently attaches to pathogen surfaces or immune complexes, serving as an opsonin and providing a scaffold for the assembly of the C3 convertase (C4b2a), which is essential for downstream complement activation and pathogen elimination.
C4 exists as two highly polymorphic isotypes, C4A and C4B, encoded within the major histocompatibility complex (MHC) on chromosome 6.
C4A preferentially forms amide bonds with protein antigens, while C4B forms ester bonds with carbohydrate antigens.
Genetic variation in C4 gene copy number and structure influences plasma C4 levels and susceptibility to autoimmune diseases, such as systemic lupus erythematosus.
Deficiency or dysfunction of C4 impairs immune complex clearance and increases susceptibility to infections and autoimmunity..
Complement component 4 (C4), in human protein involved in the intricate complement system, originating from the human leukocyte antigen (HLA) system.
It serves a number of critical functions in immunity, tolerance, and autoimmunity with the other numerous components.
C4 is a crucial factor in connecting the recognition pathways of the overall system instigated by antibody-antigen (Ab-Ag) complexes to the other effector proteins of the innate immune response.
A dysfunctional complement system can lead to fatal diseases and infections.
The C4 protein consists of 3 subunits (α, β, and γ) having molecular weights (MWs) of ~95,000, 78,000, and 31,000, respectively and they are all joined by interchain disulfide bridges.
C4 genes have a complex pattern of variation in gene size, copy number, and polymorphisms.
The liver contains the majority of C4 transcripts throughout the body, with moderate quantities were expressed in adrenal cortices/medulla, thyroid, and kidney.
Components and enzymes of the classical and alternative pathways of the complement cascade, which provides a complementary means for human and other systems to defend against foreign pathogens.
As noted, C4 (mixture of C4A and C4B) participates in all three of the complement pathways classical, alternative, and lectin:the alternative pathway is triggered spontaneously, while the classical and lectin pathways are elicited in response to the recognition of particular microbes.
All three pathways converge at a step in which complement protein C3 is cleaved into proteins C3a and C3b, which results in a lytic pathway and formation of a macromolecular assembly of multiple proteins, termed the membrane-attack complex (MAC), which serves as a pore in the membrane of the targeted pathogen, leading to invading cell disruption and eventual lysis.
In the classical pathway, the complement component termed C1s, a serine protease, is activated by upstream steps of the pathway, resulting in its cleavage of the native, parent ~200 kilodalton (kDa) C4 protein—composed of three chains.
The C4 is cleaved by the protease into two parts, a peptide C4a, small at ~9 kDa, and anaphylotoxic, and the higher molecular weight protein C4b, at about 190 kDa.
C4b interacts with protein C2.
C1s, then cleaves C2 into two parts, termed C2a and C2b, with C2b being released, and C2a remaining in association with C4b; the C4b-C2a complex of the two proteins then exhibits a further system-associated protease activity toward protein C3 (cleaving it), with subsequent release of both proteins, C4b and C2a, from their complex (whereupon C4b can bind another protein C2, and conduct these steps again).
C4b is regenerated, and a cycle is created, the C4b-C2a complex with protease activity has been termed the C3 convertase.
The C4 gene is also being investigated for the role it may play in schizophrenia risk and development.
Substantial data from all over the world has been collected and analyzed to determine that
Schizophrenia, indeed, has a strong genetic relationship with a region in the MHC locus on chromosome arm 6.
C4A expression levels is most strongly correlated with schizophrenia.
In addition, they have discovered a mechanism by which schizophrenia could arise from the genetic predisposition of the human complement C4.
Four common structural variations discovered in genome-wide association studies (GWAS) studies have pointed to the high turnout of schizophrenia.
Possibly, the higher levels of expression of C4 protein due to pattern of variants of the C4 gene, allows for the unwanted increase in synaptic pruning.