CR1 - complement C3b/C4b receptor 1|Elisa - Clia - Antibody - Protein

Background

CR1 (Complement Receptor 1), also known as CD35, is a membrane-bound glycoprotein that plays a key role in the immune system, primarily in mediating the clearance of immune complexes, apoptotic cells, and pathogens through its interaction with components of the complement system. CR1 acts as a receptor for complement proteins C3b and C4b, which are opsonins involved in the activation of the classical and alternative complement pathways. These pathways are critical for enhancing phagocytosis and immune complex clearance, ultimately contributing to host defense against infections.

CR1 is expressed on a variety of immune cells, including erythrocytes (red blood cells), leukocytes, monocytes, macrophages, neutrophils, B cells, follicular dendritic cells, and kidney podocytes. The expression pattern of CR1 allows it to fulfill diverse immunological functions, such as regulating complement activation, promoting phagocytosis, and serving as a cofactor for complement cleavage and degradation.

Its crucial role in immune regulation, clearance of pathogens, and modulation of complement activation highlights its significance in maintaining immune homeostasis and preventing damage to host tissues. Dysregulation of CR1 function or expression has been associated with various diseases, including autoimmune disorders, infectious diseases, and renal diseases.

Protein Structure

CR1 is a transmembrane glycoprotein with a molecular weight of approximately 190-250 kDa, depending on the degree of glycosylation. The CR1 protein is encoded by the CR1 gene, located on chromosome 1q32, within the regulators of complement activation (RCA) gene cluster. The structural architecture of CR1 is crucial for its function in complement regulation, and it consists of the following key domains:

Extracellular Domain:

• The extracellular domain of CR1 is large and consists of 30 short consensus repeats (SCRs), each approximately 60 amino acids long. These SCRs are also referred to as complement control protein (CCP) domains or sushi domains. The SCRs are arranged in tandem and are responsible for binding to complement proteins C3b and C4b.
• SCRs are divided into four long homologous repeats (LHRs), designated as LHR-A, LHR-B, LHR-C, and LHR-D. Each LHR contains 7-8 SCRs and contributes to the complement-binding activity of CR1.
• The interaction of CR1 with complement components, particularly C3b and C4b, occurs primarily through specific SCRs within the LHRs. For instance, LHR-A and LHR-B are involved in binding C3b, while LHR-C and LHR-D bind to C4b.
• This extracellular domain plays a key role in mediating the opsonization and clearance of pathogens, immune complexes, and damaged cells by interacting with complement-opsonized targets.

Transmembrane Domain:

• CR1 has a single transmembrane helix that anchors it within the plasma membrane. This domain is hydrophobic, typical of transmembrane proteins, and allows CR1 to be stably embedded in the lipid bilayer.
• The transmembrane region does not directly participate in ligand binding but is essential for positioning the extracellular domain on the cell surface where it can interact with complement-opsonized targets.

Cytoplasmic Tail:

• The cytoplasmic domain of CR1 is relatively short (43 amino acids), but it plays an important role in signal transduction and intracellular trafficking. This domain interacts with cytosolic proteins that regulate endocytosis, phagocytosis, and recycling of CR1 to and from the plasma membrane.
• Although the cytoplasmic tail lacks classical signaling motifs, it is involved in processes like phagocytosis and recycling of immune complexes via interactions with adaptor proteins.

The highly glycosylated nature of CR1, with N-linked glycosylation sites, further contributes to its stability, structural integrity, and function. The glycosylation pattern can also influence CR1's interactions with other proteins and its susceptibility to proteolytic cleavage, which is important in the regulation of its activity on the cell surface.

Classification and Subtypes

CR1 is part of the RCA (Regulators of Complement Activation) gene family, which includes other key complement regulators like CR2 (CD21), factor H, and decay-accelerating factor (DAF). CR1 is structurally similar to these proteins due to its multiple SCR domains, which mediate complement regulation.

CR1 has several polymorphic variants, primarily differing in the number of SCRs, which result in differences in protein length and function. These polymorphisms are inherited and lead to the existence of different isoforms of CR1:

• The most common isoform is the CR1*1 isoform (also called CR1-F), which contains the full complement of 30 SCRs.
• Other variants, such as CR1*2 and CR1*3, have deletions or duplications of specific SCRs, affecting their binding affinity to complement components and altering their functional properties.
• Soluble CR1 (sCR1) has also been identified in the circulation, which may arise from proteolytic cleavage of membrane-bound CR1 or may be secreted by specific cells. Soluble CR1 retains complement regulatory activity and can modulate immune responses.

Polymorphisms in the CR1 gene, particularly those that affect CR1 expression levels or function, are associated with susceptibility to diseases such as systemic lupus erythematosus (SLE), Alzheimer's disease, and malaria.

Function and Biological Significance

The primary function of CR1 is to mediate the regulation of the complement system, particularly through interactions with C3b and C4b. CR1 has several key roles:

Complement Regulation:

• CR1 acts as a cofactor for factor I, an enzyme that cleaves and inactivates C3b and C4b. By promoting the degradation of C3b and C4b, CR1 limits the formation of the C3/C5 convertases, which are essential for the amplification of complement activation.
• CR1 also mediates the decay-accelerating activity for the C3 convertase (C4b2a) and the C5 convertase by promoting the dissociation of these enzymatic complexes, thereby preventing excessive complement activation that could lead to tissue damage.

Immune Complex Clearance:

• CR1 on erythrocytes binds to immune complexes opsonized with C3b and facilitates their removal from circulation by transporting them to the liver and spleen, where they are cleared by phagocytes. This mechanism is crucial for maintaining immune homeostasis and preventing the accumulation of harmful immune complexes in tissues.
• CR1 plays a pivotal role in the clearance of apoptotic cells, debris, and microbial pathogens coated with complement, thus preventing autoimmune reactions and maintaining tissue integrity.

Phagocytosis:

• CR1 on phagocytic cells such as macrophages and neutrophils enhances the uptake of complement-opsonized pathogens. By engaging complement-opsonized particles via CR1, these cells can efficiently engulf and destroy microbes or other targets, contributing to innate immune defense.
• CR1 is particularly important for the efficient clearance of immune complexes and pathogens in tissues with high complement activity, such as the spleen, liver, and kidney.

Modulation of Inflammatory Responses:

• CR1 can modulate the intensity of inflammatory responses by regulating complement activation. By limiting the deposition of C3b and C4b on host tissues, CR1 prevents the formation of the membrane attack complex (MAC) and subsequent tissue damage.
• CR1's ability to inhibit complement-mediated inflammation makes it an important molecule in preventing pathological conditions such as autoimmunity and chronic inflammation.

Clinical Issues

Mutations, polymorphisms, or deficiencies in CR1 expression are associated with several diseases, which highlight its importance in immune regulation:

Systemic Lupus Erythematosus (SLE):

• Low expression levels of CR1 are associated with increased susceptibility to SLE, an autoimmune disease characterized by the deposition of immune complexes in tissues. Impaired immune complex clearance due to CR1 deficiency may contribute to the pathogenesis of lupus.

Alzheimer's Disease:

• Genetic polymorphisms in the CR1 gene have been implicated in the risk of developing Alzheimer's disease. CR1 may influence the clearance of amyloid-beta plaques through its role in immune complex clearance, suggesting a link between complement regulation and neurodegenerative diseases.

Malaria:

• CR1 is involved in the pathogenesis of malaria caused by Plasmodium falciparum, where the parasite uses CR1 on erythrocytes to bind and invade host cells. Certain polymorphisms in CR1 are associated with resistance to severe malaria, indicating its relevance in infectious disease susceptibility.

Kidney Diseases:

• CR1 expression on glomerular podocytes is important for the clearance of immune complexes in the kidney. Dysregulation of CR1 in the kidney is associated with immune-mediated kidney diseases, such as membranous nephropathy and glomerulonephritis.

Summary

CR1 is a critical receptor in the regulation of the complement system, mediating the clearance of immune complexes, apoptotic cells, and pathogens. Its role in maintaining immune homeostasis, limiting inflammation, and promoting phagocytosis makes it essential for preventing autoimmune and inflammatory diseases. Structural variations and polymorphisms in CR1 have profound clinical implications, influencing susceptibility to diseases like SLE, Alzheimer's disease, and malaria. Further understanding of CR1's structure-function relationship and its role in disease could provide new insights into therapeutic interventions targeting complement-mediated pathologies.