Complement Component C5

The complement system relies on the precise orchestration of over 30 proteins to defend against pathogens and maintain homeostasis. At the heart of this system lies complement component C5, a glycoprotein whose cleavage into bioactive fragments C5a and C5b drives both protective immunity and pathological inflammation. As a central node in the complement cascade, C5 has emerged as a high-value therapeutic target, offering opportunities to modulate immune responses in diseases ranging from rare hematologic disorders to neurodegenerative conditions.

What is Complement C5?

C5 is the fifth component of the complement system. It is a 190 kDa glycoprotein central to the complement system, encoded by the C5 gene located on chromosome 9 in humans. Structurally, it comprises α- and β-chains linked by a disulfide bond, with a domain organization resembling complement component C3 but distinct functional features. Its activation occurs via C5 convertases, which cleave C5 into:

• Complement component C5a: A 74-amino acid anaphylatoxin that binds G protein-coupled receptors (C5aR1 and C5aR2), inducing chemotaxis, cytokine release, and vascular permeability.
• Complement component C5b: The initiator of the membrane attack complex (MAC), a pore-forming structure (C5b-9) that lyses pathogens but can also damage host cells.

Fig.1 Structure of C5.^1,3

Structural features of the C5 protein:

• Domain flexibility: The C345C domain, critical for interactions with convertases and regulators, is flexibly attached to the core structure, enabling conformational shifts during activation.
• Activation-induced changes: Cleavage by C5 convertases (e.g., CVF, Bb) at Arg74-Leu75 in the α-chain triggers a conformational rearrangement, exposing transient binding sites for C6 and initiating MAC assembly. Unlike C3, C5 lacks a thiol ester bond, relying instead on non-covalent interactions for membrane targeting.

Functional Role of C5 in the Complement System

Complement component C5 plays a pivotal role in the complement system, bridging innate immune defenses and inflammatory responses. Its cleavage into C5a and C5b drives two critical pathways: inflammatory signaling and MAC formation.

Table 1 Key functional roles of C5 fragments.

Fig. 2 The generation of C5a and C5b.^{2, 3}

This dual functionality positions C5 at a critical juncture: while C5a amplifies inflammation, MAC formation provides direct microbial killing. Regulatory proteins like CD59 and vitronectin prevent uncontrolled MAC activity on host cells.

C5 Functional Test

The C5 functional test is a specialized assay used to assess the activity of complement component C5 in serum samples. This test is crucial for diagnosing C5 deficiency and investigating complement system abnormalities.

Hemolytic assays are one of the primary complement C5 function tests that may be performed. By combining patient serum with a C5-deficient serum, component C5 activity is assessed. The serum mixture's lytic activity is evaluated against SRBC or sensitized, tagged liposomes. If lysis happens, the C5 must originate from the patient's serum.

With years of experience in complement tests, Creative Biolabs supports complement C5 functional tests to help advance your programs. Notably, we can tailor complement test assays based on multi-disciplinary scientists and comprehensive platforms.

Hemolytic assays

Fig.3 Workflow of C5 functional test with hemolytic assays.

C5 ELISA

Fig.4 Workflow of C5 functional test with ELISA.

C5 in Health and Disease

C5 dysregulation can lead to various pathological conditions due to its crucial role in the complement system. The main implications include:

• Increased susceptibility to infections.
• Autoimmune and inflammatory conditions
• Complement-mediated diseases
• Neurological disorders
• Other implications

Table 2 The potential relationship between C5 and diseases.

Component C5 Based Therapy

C5 appears to be an attractive therapeutic target to control because of the release of the potent proinflammatory peptide C5a and to the assembly of the terminal complex responsible for tissue damage and inflammation to fight infection, clear immunocomplexes and maintain self-tolerance.

Various types of antibodies and compounds such as peptides or non-peptides have actively been developed, and these substances act as inhibitors of complement components C5 and C5a and antagonists of the C5a receptor, which selectively allows inhibition of the C5b and C5a-mediated responses while leaving the rest of complement unaffected. These C5 and C5a receptor antagonists may be efficacious at treating various inflammatory diseases involving complements.

Table 3 C5 in drug development.

At Creative Biolabs, we leverage decades of experience to advance C5-focused therapies through:

• Total Complement Activity Test
• C5 Complex Functional Test
• C5a Functional Test
• C5b Functional Test
• C5 Convertase Functional Test
• C5 Antibodies
• C5 Related Proteins
• C5 Related Array Kits
• C5 Related Aptamer
• C5 Related Inhibitors

If you want more information, please feel free to contact us.

References

1. Aleshin, Alexander E., et al. "Crystal structure of C5b-6 suggests structural basis for priming assembly of the membrane attack complex." Journal of Biological Chemistry 287.23 (2012): 19642-19652. https://doi.org/10.1074/jbc.M112.361121
2. Horiuchi, Takahiko, and Hiroshi Tsukamoto. "Complement-targeted therapy: development of C5-and C5a-targeted inhibition." Inflammation and regeneration 36.1 (2016): 1-5. https://doi.org/10.1186/s41232-016-0013-6
3. under Open Access license CC BY 4.0, without modification.

• Complement Component C1
• Complement Component C2
• Complement Component C6
• Complement Component C7
• Complement Component C8
• Complement Component C9
• Complement Component Factor B/CFB
• Complement Component Factor D/CFD/Adipsin
• Complement Component Factor Properdin/CFP
• Complement Component C3
• Complement Component Factor I/CFI
• Complement Component C4
• Complement Component C5a
• Complement Component C5b