Complement Regulator of Complement System: Protectin / CD59

To maintain immune homeostasis, the body utilizes several complement regulatory proteins. Among them, Protectin, also known as CD59, stands out as a critical membrane-bound inhibitor of the membrane attack complex (MAC). At Creative Biolabs, we offer a wide range of solutions for complement-based research, including component-related services and complement system-realted products for CD59, which can help you further reveal its mechanism of action in different physiological processes.

What is CD59?

CD59, encoded by the CD59 gene, is a small glycosylphosphatidylinositol (GPI)-anchored protein expressed on virtually all human cell surfaces. It plays a central role in regulating the terminal pathway of the complement cascade by inhibiting MAC formation.

• Molecular weight: ~18–25 kDa (due to glycosylation)
• Structure: Single GPI-anchored polypeptide with disulfide bonds
• Localization: Plasma membrane, enriched in lipid rafts

The human CD59 gene is located on the broken arm of chromosome 11 and is about 27kb long. Its protein consists of 128 amino acids, and the 25 amino acid residues at the N-terminus are signal peptides. The C-terminus is anchored to the cell membrane surface by GPI, and participates in signal transduction through GPI and lipid raft. CD59 protein contains 5 disulfide bonds, which not only maintains its spatial structure, but also maintains its molecular properties stable.

Fig. 1 Protein structure of CD59.¹

Structurally, CD59 is a small, highly glycosylated GPI connexin protein with a broad expression profile. Functionally, CD59's role in complement regulation is clearly defined, but studies have shown that changes in its anchoring mode and location can trigger a series of signal transmissions independent of the complement system, suggesting that CD59 has a role other than complement inhibitors.

Biological Functions of CD59

The tissue expression of CD59 is very extensive, and it is expressed in lung, liver, kidney, heart, skin, nervous system and various blood cells. Its main function is to bind to C8α and C9 in the end stage after activation of the complement system, and inhibit MAC formation, which in turn protects cells from MAC-mediated cell lysis effects. In addition, CD59 also performs a number of functions that are not related to the complement system. It can be used as a natural ligand of CD2 to participate in T cell adhesion and transduction of cell activation signals, to participate in the proliferation and differentiation of B cells and natural killer cells, and to participate in apoptosis signals.

Table 1 Biological functions and mechanisms of CD59.

The mechanism by which CD59 functions is highly specific.

• When C5b-8 and C9 assemble to form the MAC, CD59 binds to C8α and C9.
• This prevents the insertion and polymerization of C9 into the membrane.
• As a result, cell lysis is averted.

This function is essential for protecting erythrocytes, neurons, and endothelial cells, especially under inflammatory conditions.

CD59 Functional Test

The CD59 test is a specialized assay designed to evaluate the biological activity of CD59 in regulating the terminal pathway of the complement system. CD59 plays a crucial role in inhibiting the formation of the MAC by binding to complement components C8 and C9, thereby protecting host cells from lysis.

This test is typically based on complement-mediated hemolysis or cell lysis assays, where the protective effect of CD59 is measured by its ability to inhibit MAC-induced cell damage.

Table 2 Available formats of CD59 test.

At Creative Biolabs, our CD59 functional assay is optimized to quantitatively assess the inhibitory activity of CD59 in various biological samples, including recombinant proteins, patient-derived cells, and engineered models.

• Confirming CD59 activity in recombinant protein products
• Evaluating CD59-mediated complement resistance in cell lines
• Screening therapeutic inhibitors or enhancers of CD59 function
• Supporting preclinical studies on immune evasion mechanisms

CD59 in Health and Disease

Alterations in CD59 expression or function have been implicated in a wide range of human diseases. These can involve either loss of function, leading to increased susceptibility to complement-mediated damage, or overexpression, which contributes to immune evasion in pathological states such as cancer.

• Paroxysmal nocturnal hemoglobinuria (PNH) - In PNH, a somatic mutation in the PIGA gene disrupts GPI anchor synthesis, leading to CD59 deficiency on red blood cells.
• Neurological disorders - CD59 deficiency or dysfunction has been linked to chronic inflammatory demyelinating polyneuropathy (CIDP) and multiple sclerosis, where aberrant complement activation contributes to nerve damage.
• Autoimmune diseases - In conditions like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), reduced CD59 levels may exacerbate tissue damage due to inadequate complement regulation.
• Cancer - Many tumor types, including breast, ovarian, and lung cancers, upregulate CD59 expression to evade complement-mediated lysis.

Table 3 Summary table: CD59 in health vs. disease.

CD59 in Drug Development

CD59 has emerged as a pivotal target and tool in the field of complement-targeted drug development. As a native inhibitor of MAC formation, CD59 plays a dual role: on one hand, it offers therapeutic potential in complement-mediated disorders where protection against MAC is beneficial; on the other hand, its overexpression in cancer and pathogen-infected cells poses a challenge to complement-activating therapies, thus warranting inhibitory strategies.

Table 4 Therapeutic strategies involving CD59.

Creative Biolabs offers the following tailored services to support CD59-targeted or CD59-modulated drug development:

• Total Complement Activity Test
• Individual Components Activity Test
• CD59 Antibodies
• CD59 Related Proteins
• CD59 Related Array Kits
• CD59 Related Lysates
• CD59 Related Aptamers

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

Reference

1. From Wikipedia: By Emw - Own work, CC BY-SA 3.0 https://commons.wikimedia.org/wiki/File:Protein_CD59_PDB_1cdq.png

• C1 Inhibitor/C1INH/SERPING1
• Vitronectin/VTN
• Clusterin/CLU