Complement Component Protein

The complement system consists of a large number of distinct plasma proteins that react with one another to opsonize pathogens and induces a series of inflammatory responses which are helpful to fight infection. There are ten major complement proteins, C1, C2, C5, C6, C7, C8, C9, factor B, factor D and factor properdin. With years of exploration and expansion, Creative Biolabs offers comprehensive one-stop services for complement therapeutics.

  1. Complement Component C1

Complement component C1 is a 750 kD glycoprotein that requires calcium or other specific metal ions to maintain its native structure and function. The classical pathway of complement is activated upon binding of the C1 complex. C1 comprises two weakly interacting subunits, C1q and C1r2s2. C1 circulates in a precursor state and C1 activation can be induced by immune complexes or certain nonimmune substances. With C1 binding to an immune complex, the strength of interaction between C1q and C1r2s2 increases. C1 functions are controlled by the serum glycoprotein C1-inhibitor which blocks the enzymatic activities of activated C1. The organization of the C1 subunits and activation of the classical pathway are shown in Figure 1.

Structure and activation of C1

Fig.1 Structure and activation of C1. (Mortensen, 2017)

  1. Complement Component C2

component C2 is encoded by a gene within the MHC on chromosome 6. C2 is a multidomain serine protease that provides catalytic activity to the C3 and C5 convertases of the classical pathway and the lectin pathway of complement. C2 shares homology with the classical serine proteinases, but it is unusual in having a catalytic chain with a much extended N-terminus. Deficiency of C2 has been associated with certain autoimmune diseases.

  1. Complement Component C5

The complement system is activated via three routes, the classical pathway, the alternative pathway and the lectin pathway, all leading to the activation of C5 and the terminal pathway. Activation of C5 generates the potent anaphylatoxin C5a and leads to pathogen lysis, inflammation and cell damage. The therapeutic significance of C5 inhibition is demonstrated by Eculizumab. At present, C5 is a validated drug target and an anti-C5 antibody (Soliris) is an approved therapy for paroxysmal nocturnal hemoglobinuria.

Activation of C5 by C5 convertase leads to the generation of C5a an activities

Fig.2 Activation of C5 by C5 convertase leads to the generation of C5a an activities. (Horiuchi, 2016)

  1. Complement Component C6

Complement component C6 is a part of the lytic membrane attack complex (MAC) formed during complement activation. In C6, the regulatory segment includes four auxiliary domains that stabilize the closed conformation, inhibiting release of membrane-inserting elements. Deficiency of C6 causes enhanced susceptibility to gram-negative bacterial infections or recurrent bacterial infection.

  1. Complement Component C7

Complement component C7 is a single-chain glycoprotein consisting of a single domain (MACPF) and eight cysteine-rich modules homologous. C7 plays an integral role in the assembly of this complex within target cell membranes. Deficiency of C7 leads to the dysfunction of MAC.

Crystal structure for complement component C7

Fig.3 Crystal structure for complement component C7. (Barnum, 2017)

  1. Complement Component C8

Complement component C8 is composed of three subunits (alpha, beta and gamma). Together with C5, C6, C7 and C9, C8 assembles on bacterial membranes to form the lethal pore-like MAC. Deficiency of C8 is a very rare primary immunodeficiency, associated with invasive, recurrent infections mainly caused by Neisseria species.

  1. Complement Component C9

Complement component C9 is the last protein that binds to the assembling MAC of complement, completing the sequence of events that leads to the destruction of target membranes. During MAC assembly, up to 18 molecules of C9 can bind to each C5b-8 complex, forming stable ion pores or channels in membranes and leading to lysis and death of the target cell. Deficiency of C9 is inherited as an autosomal recessive trait and is related to complement deficiency and meningococcal meningitis.

Schematic diagram of MAC

Fig.4 Schematic diagram of MAC.

  1. Complement Component Factor B/CFB

Complement component factor B, a single-chain, 93 kDa pcolypeptide, is a component of the alternative pathway of complement. Factor B circulates as an inactive proenzyme and only becomes activated after cleavage by factor D. It is generated as a single-chain protein, and cleavage by factor D generates two peptide fragments, Ba (33 kDa) and Bb (60 kDa). When activated, it provides the catalytic activity of the alternative pathway C3 and C5 convertases. Deficiency of factor B is related to hemophilia b and pulmonary hypertension.

  1. Complement Component Factor D/CFD/Adipsin

Complement component factor D is a serine protease consisting of a single polypeptide of 228 amino acids. The function of factor D is to cleave its unique substrate to generate the C3 convertases C3(Hc2O)Bb and C3bBb. Factor D participates in the amplification loop which contributes significantly to responses elicited by the classical pathway and the lectin pathway. Factor D deficiency is an autosomal recessive immunologic disorder characterized by increased susceptibility to bacterial infections, particularly Neisseria infections.

  1. Complement Component Factor Properdin/CFP

Complement component factor properdin is a key positive regulator of the alternative pathway by significantly increasing the half-life of the C3 and C5 convertases. Properdin is also an initiator of the alternative pathway. The properdin gene is located on the X chromosome and deficiency of factor properdin leads to impaired alternative pathway function, leaving patients highly susceptible to fulminant meningococcal infections.

Schematic diagram of properdin

Fig.5 Schematic diagram of properdin. (Choi, 2012)

Creative Biolabs offers innovative complement drug discovery services targeting various complement components (including proteases, receptors, and regulators) for different indications. Please directly contact us and consult our technical supports for more details.

References

  1. Mortensen, S. A.; et al. Structure and activation of C1, the complex initiating the classical pathway of the complement cascade. Proceedings of the National Academy of Sciences. 2017, 114(5): 986-991.
  2. Horiuchi, T.; Tsukamoto, H. Complement-targeted therapy: development of C5-and C5a-targeted inhibition. Inflammation and regeneration. 2016, 36(1): 11.
  3. Barnum, S. R.; Schein, T. N. (Eds.). The complement factsbook. Academic Press. 2017.
  4. Choi, Sangdun, ed. Encyclopedia of Signaling Molecules. Vol. 337. New York: Springer, 2012.

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