Complement Regulator of Complement System: Clusterin / CLU

• Clusterin (CLU), also known as apolipoprotein J (ApoJ), is a multifunctional glycoprotein ubiquitously expressed across tissues and fluids. It plays essential roles in complement regulation, lipid transport, apoptosis, and cellular stress responses. Among its diverse biological functions, its involvement as an extracellular chaperone and regulator of the complement cascade has attracted considerable interest in both basic immunology and therapeutic development.
• At Creative Biolabs, we provide a comprehensive suite of complement system research tools, including functional assays, antibody development, and therapeutic validation services specifically tailored to CLU and other complement regulators.

What is Clusterin?

CLU is a heterodimeric glycoprotein comprising two disulfide-linked subunits generated through post-translational cleavage of a single precursor. It is predominantly secreted but also has intracellular isoforms involved in nuclear and cytosolic signaling.

The mature form of human secreted CLU is a secreted heterodimeric glycoprotein of 75-80 kDa. As other secreted proteins, translation of CLU mRNA results in a preprotein composed of 449 amino acids (psCLU). The psCLU is transported into the Golgi and then heavily glycosylated. A proteolysis process removes the leader signal polypeptide and cleaves the preprotein into an α-chain and a β-chain. The two chains are linked in an antiparallel fashion through five disulfide bonds.

Table1 The physicochemical properties of the mature protein

Structural predictions performed in rat, human, and bovine CLU showed highly conserved amphipathic α-helices regions with hydrophobic and hydrophilic features. Intrinsically disordered regions have been also predicted, such as coil-like and molten globule-like regions. These domains are predominantly located at the N- and C- termini of the α- and β-chains. Predicted ordered regions have been found around the conserved cysteine residues implicated in the formation of the five disulfide bonds. A short disordered region comprises the posttranslational cleavage site generating α- and β-chains. The structure of CLU is supposed to be highly flexible, due to the presence of amphipathic α-helix ordered structures and disordered regions. This feature may account for its strong binding activity of unfolded proteins, and/or other putative partners. In fact, CLU forms oligomers, and it can interact with distinct ligands forming complexes with different molecular mass and diameter.

Fig. 1 Clusterin gene and protein structure.^{1, 2}

Biological Functions of Clusterin

Although CLU was identified more than 30 years ago, an understanding of its biological functions is still elusive. Data showed that CLU inhibits the activity of the complement system. CLU binds to the terminal C complexes and prevents their insertion into cell membranes. The resulting complexes are soluble and unable to induce complement lysis. CLU specifically binds to C7, the β-subunit of C8 and C9. The conformational changes occurring during the formation of MAC expose the interaction sites for CLU that binds to a structural motif common to C7, C8 and C9β inhibiting the correct complex assembly.

It has been speculated that one of CLU in vivo function is to control terminal complement-mediated damage, preventing uncontrolled membrane attack complex (MAC) activity. CLU has been found on MAC bound to circulating immune complexes (CIC) in systemic lupus erythematosus patients. The presence of CLU has been associated with a protective function from complement-mediated injury or from potentially damaging agents of the extracellular environment. The association between CLU and complement proteins has been reported in different human pathological conditions suggesting a protective effect of CLU under stress conditions.

In summary, the role of CLU in complement regulation includes:

• Inhibition of MAC formation
• Synergy with Vitronectin (VTN)

This regulation is particularly important in diseases where chronic inflammation or complement overactivation is observed, such as age-related macular degeneration (AMD), systemic lupus erythematosus (SLE), and Alzheimer's disease.

Clusterin Test

CLU is ubiquitously expressed in almost all mammalian tissues and has been found in all human body fluids and analyzed. CLU circulates in human plasma at a concentration of 150-540 μg/mL. It is about 10 times higher in human seminal plasma.

CLU testing is a critical tool for understanding its regulatory role in the complement system and its potential as a biomarker in disease monitoring. At Creative Biolabs, we offer a full suite of CLU assay solutions to support both research and clinical development.

Available assays include:

Table 2 Clusterin testing.

All tests are fully customizable to your sample type, assay sensitivity, and experimental goals and can be used in a wide range of applications.

• Monitoring complement regulatory activity
• Validating Clusterin-targeted therapies
• Analyzing biomarker levels in neurological, renal or autoimmune diseases
• Supporting drug discovery processes involving complement regulation

Clusterin in Health and Disease

CLU is a highly versatile protein implicated in a wide range of physiological and pathological processes. Its role as a complement inhibitor, molecular chaperone, and lipid-binding glycoprotein positions it at the crossroads of immunity, neurobiology, and cellular homeostasis. Dysregulation of CLU expression or function is associated with numerous human diseases, making it a key focus in biomarker discovery and therapeutic targeting.

Table 3 Clinical implications of Clusterin.

Creative Biolabs offers integrated solutions to investigate CLU's roles across health and disease.

Clusterin as a Therapeutic Target

CLU has garnered increasing attention as a therapeutic target and candidate due to its unique multifunctionality in modulating complement activity, protecting stressed cells, and stabilizing misfolded proteins.

Table 4 Current and emerging therapeutic strategies.

Whether you're developing CLU-based biologics or exploring its pathway for novel drug targets, Creative Biolabs is your trusted CRO partner for advancing complement-targeted therapeutics. We bring two decades of experience in complement biology, protein engineering, and translational immunology. Our services and products related to CLU include:

• Complement Function/Activity Test
• Vitronectin Antibodies
• Vitronectin Related Proteins
• Vitronectin Related Assay Kits
• Vitronectin Related Lysate

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

References

1. Foster, Evangeline M., et al. "Clusterin in Alzheimer's disease: mechanisms, genetics, and lessons from other pathologies." Frontiers in neuroscience 13 (2019): 164. https://doi.org/10.3389/fnins.2019.00164
2. under Open Access license CC BY 4.0, without modification

• C1 Inhibitor/C1INH/SERPING1
• Protectin/CD59
• Vitronectin/VTN