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Chemistry and molecular genetics of C1q
1Department of Biochemistry, University of Oxford, U.K.
Insights
The complement component C1q, crucial for immune responses, has a hexameric structure. Genetic analysis revealed a point mutation in the C1q B chain causes deficiency, impacting immune complex activation.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- C1q is the first component of the complement system, essential for initiating immune responses.
- It possesses a hexameric structure with globular heads and collagen-like stalks, mediating interactions with immune complexes and cell receptors.
- Structurally similar proteins like mannan-binding protein also interact via collagen-like regions.
Purpose of the Study:
- To elucidate the structure and function of C1q in complement activation.
- To investigate the genetic basis of C1q deficiency.
- To understand the molecular interactions of C1q with immune complexes and cell surfaces.
Main Methods:
- Structural analysis of C1q's hexameric form.
- Utilizing cDNA and genomic clones for gene location and organization studies.
- DNA analysis of C1q-deficient individuals to identify mutations.
Main Results:
- C1q's structure comprises six globular heads linked by collagen-like stalks to a central region.
- Activation by immune complexes involves C1q heads binding to IgG or IgM.
- A single point mutation in the C1q B chain gene was identified as the cause of C1q deficiency in one individual.
Conclusions:
- C1q's unique structure facilitates its role in initiating complement activation.
- Genetic defects, such as point mutations in the C1q B chain, can lead to complement deficiency.
- Understanding C1q's structure-function relationship and genetic basis is vital for immunology research.
Abstract:
C1q has a hexameric structure with six triple helices being formed between the collagen-like sequences of its 6A, 6B and 6C chains and globular 'heads' being formed from the C-terminal portions of these chains. Thus the molecule is composed of six globular 'heads' linked via six collagen-like 'stalks' to a fibril-like central region. The collagen-like regions interact with the C1r2-C1s2 proenzyme complex to yield C1, the first component of complement. Activation of C1 by immune complexes is mediated by the ionic binding of two, or more, of the 'heads' of C1q to the C gamma 2 domains of IgG or C mu 3 domains of IgM. Removal of the activated C1r2-C1s2 complex by C1-inhibitor leaves the collagen-like 'stalks' of C1q free to bind to cell-surface C1q-receptors. Three other proteins, conglutinin, mannan-binding protein and lung-surfactant protein are structurally similar in many respects to C1q and may also bind to receptors via their collagen-like regions although they show carbohydrate binding properties via their globular 'heads'. The availability of cDNA and genomic clones for the chains of C1q has allowed studies on their location and organisation and also on the analysis of DNA from C1q deficient individuals. The human A and B chain genes are located approx. 20kb apart on chromosome 1p, each gene being approx. 2kb long and each containing one intron of about 1kb. Genetic C1q deficiency in one individual has been shown to be due to the generation of a stop codon by a single point mutation at residue 150 in the coding region of the B chain.