Complement receptor 1
Encyclopedia
Erythrocyte complement receptor 1 (CR1, also known as CD35
, C3b/C4b receptor and immune adherence
receptor) is a human gene
.
This protein
encoded by this gene is a member of the regulators of complement activation (RCA) family and is located in the 'cluster RCA' region of chromosome 1. The gene encodes a monomeric single-pass type I membrane glycoprotein found on erythrocytes, leukocytes, glomerular podocytes, and splenic follicular dendritic cells. The Knops blood group system is a system of antigens located on this protein. The protein mediates cellular binding to particles and immune complexes that have activated complement. Decreases in expression of this protein and/or mutations in its gene have been associated with gallbladder carcinomas, mesangiocapillary glomerulonephritis, systemic lupus erythematosus and sarcoidosis. Mutations in this gene have also been associated with a reduction in Plasmodium falciparum
rosetting, conferring protection against severe malaria. Alternate allele-specific splice variants, encoding different isoforms, have been characterized. Additional allele specific isoforms, including a secreted form, have been described but have not been fully characterized.
In primates, CR1 serves as the main system for processing and clearance of complement opsonized immune complexes. It has been shown that CR1 can act as a negative regulator of the complement
cascade, mediate immune adherence
and phagocytosis and inhibit both the classic and alternative pathways. The number of CR1 molecules decreases with aging of erythrocytes in normal individuals and is also decreased in pathological conditions such as systemic lupus erythematosus
(SLE), HIV
infection, some s and other conditions featuring immune complex
es. In mice, CR1 is an alternatively spliced variant of the complement receptor 2 (CR2) gene.
Certain alleles of this gene have been statistically associated with an increased risk of developing late-onset Alzheimer's Disease
.
Factor H
, another immunoregulatory protein, also maps to this location.
s spanning 133kb encoding a protein
of 2039 amino acid
s and has a predicted molecular weight of 220 kDa. Large insertion
s and deletion
s have given rise to four structurally variant gene
s and some alleles may extend up to 160 kb and 9 additional exons. The transcription
start site has been mapped to 111 bp upstream of the translation
initiation codon ATG and there is another possible start site 29 bp further upstream. The promoter region lacks a distinct TATA box
sequence. The gene is expressed principally on erythrocytes, monocytes, neutrophils and B cells but is also present on some T lymphocytes, mast cells and glomerular podocytes.
The mean number of complement receptor 1 (CR1) molecules on erythrocytes in normal individuals lies within the range of 100-1000 molecules per cell. Two codominant allele
s exist - one controlling high and the other low expression. Homozygote
s differ by a factor of 10-20: heterozygotes
typically have 500-600 copies per erythrocyte. These two alleles appear to have originated before the divergence of the European and African populations.
, an extracellular domain of 1930 residues, a 25 residue transmembrane domain and a 43 amino acid C terminal cytoplasmic region. The leader sequence and 5'-untranslated region
are contained in one exon. The large extracellular domain of CR1, which has 25 potential N-glycosylation sites, can be divided into 30 short consensus repeats (SCRs) (also known as complement control protein
repeats (CCPs) or sushi domains), each having 60 to 70 amino acids. The sequence homology between SCRs ranges between 60 to 99 percent. The transmembrane region is encoded by 2 exons and the cytoplasmic domain and the 3'-untranslated regions are coded for by two separate exons.
The 30 or so SCRs are further grouped into four longer regions termed long homologous repeats (LHRs) each encoding approximately 45 kDa of protein and designated LHR-A, -B, -C, and -D. The first three have seven SCRs while LHR-D has 9 or more. Each LHR is composed of 8 exons and within an LHR, SCR 1, 5, and 7 are each encoded by a single exon, SCR 2 and 6 are each encoded by 2 exons, and a single exon codes for SCR 3 and 4. The LHR seem to have arisen as a result of unequal crossing over and the event that gave rise to LHR-B seems to have occurred within the fourth exon of either LHR-A or –C. To date the atomic structure have been solved for SCRs 15-16, 16 & 16-17.
s and a partial amino-terminal duplication (CR1-like gene) that encodes the short (55kDa-70kDa) forms expressed on non human erythrocytes. These short CR1 forms, some of which are glycosylphosphatidylinositol (GPI) anchored, are expressed on erythrocytes and the 220kDa molecular weight CR1 form is expressed on monocytes. The gene including the repeats is highly conserved in primates possibly because of the ability of the repeats to bind complement. LHR-A binds preferentially to the complement component C4b: LHR-B and LHR-C bind to C3b and also, albeit with a lower affinity, to C4b. Curiously the human CR1 gene appears to have an unusual protein conformation but the significance of this finding is not clear.
erythrocyte membrane protein 1 (PfEMP1) interacts with uninfected erythrocytes. This 'stickiness', known as rosetting, is believed to be a strategy used by the parasite to remain sequestered in the microvasculature to avoid destruction in the spleen
and liver
. Erythrocyte rosetting causes obstruction of the blood
flow in microcapillaries. There is a direct interaction between PfEMP1 and a functional site of complement receptor type 1 on uninfected erythrocytes.
York
(Yk) a with the following allelic pairs:
The antigen is known to lie within the CR1 protein repeats and was first described in 1970 in a 37-year-old Caucasian woman. Racial differences exist in the frequency of these antigens: 98.5% and 96.7% of American
Caucasians and Africa
ns respectively are positive for McC(a). 36% of a Mali population were Kn(a) and 14% of exhibited the null (or Helgeson) phenotype compared with only 1% in the American population. The frequencies of McC (b) and Sl (2) are higher in Africans compared with Europe
ans and while the frequency of McC (b) was similar between Africans from the USA or Mali
, the Sl (b) phenotype is significantly more common in Mali - 39% and 65% respectively. In Gambia the Sl (2)/McC(b) phenotype appears to have been positively selected - presumably due to malaria. 80% of Papua New Guinea
ns have the Helgeson phenotype
and case control studies suggest this phenotype has a protective effect against severe malaria
.
Cluster of differentiation
The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on white blood cells, providing targets for immunophenotyping of cells...
, C3b/C4b receptor and immune adherence
Immune adherence
Immune adherence was described by Nelson for an in vitro immunological reaction between normal erythrocytes and a wide variety of microorganisms sensitized with their individually specific antibody and complement; erythrocytes were observed to adhere to microorganisms...
receptor) is a human gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
This protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
encoded by this gene is a member of the regulators of complement activation (RCA) family and is located in the 'cluster RCA' region of chromosome 1. The gene encodes a monomeric single-pass type I membrane glycoprotein found on erythrocytes, leukocytes, glomerular podocytes, and splenic follicular dendritic cells. The Knops blood group system is a system of antigens located on this protein. The protein mediates cellular binding to particles and immune complexes that have activated complement. Decreases in expression of this protein and/or mutations in its gene have been associated with gallbladder carcinomas, mesangiocapillary glomerulonephritis, systemic lupus erythematosus and sarcoidosis. Mutations in this gene have also been associated with a reduction in Plasmodium falciparum
Plasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
rosetting, conferring protection against severe malaria. Alternate allele-specific splice variants, encoding different isoforms, have been characterized. Additional allele specific isoforms, including a secreted form, have been described but have not been fully characterized.
In primates, CR1 serves as the main system for processing and clearance of complement opsonized immune complexes. It has been shown that CR1 can act as a negative regulator of the complement
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
cascade, mediate immune adherence
Immune adherence
Immune adherence was described by Nelson for an in vitro immunological reaction between normal erythrocytes and a wide variety of microorganisms sensitized with their individually specific antibody and complement; erythrocytes were observed to adhere to microorganisms...
and phagocytosis and inhibit both the classic and alternative pathways. The number of CR1 molecules decreases with aging of erythrocytes in normal individuals and is also decreased in pathological conditions such as systemic lupus erythematosus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
(SLE), HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infection, some s and other conditions featuring immune complex
Immune complex
An immune complex is formed from the integral binding of an antibody to a soluble antigen. The bound antigen acting as a specific epitope, bound to an antibody is referred to as a singular immune complex....
es. In mice, CR1 is an alternatively spliced variant of the complement receptor 2 (CR2) gene.
Certain alleles of this gene have been statistically associated with an increased risk of developing late-onset Alzheimer's Disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
1q32 region
In humans, the CR1 gene is located at on the long arm of chromosome 1 at band 32 (1q32) and lies within a complex of immunoregulatory genes. In 5’-3’ order the genes in this region are: membrane cofactor protein - CR1- complement receptor type 2 - decay-accelerating factor - C4-binding protein.- Membrane cofactor protein is a widely distributed C3b/C4b binding regulatory glycoproteinGlycoproteinGlycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
of the complement system; - decay-accelerating factor (DAF: CD55: Cromer antigen) protects host cells from complement-mediated damage by regulating the activation of C3 convertases on host cell surfaces;
- complement receptor 2 is the C3d receptor.
Factor H
Factor H
Factor H is a member of the regulators of complement activation family and is a complement control protein. It is a large , soluble glycoprotein that circulates in human plasma...
, another immunoregulatory protein, also maps to this location.
Forms
The most common form of the CR1 gene (CR1*1) is composed of 38 exonExon
An exon is a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA have been removed by cis-splicing or when two or more precursor RNA molecules have been ligated by trans-splicing. The mature RNA molecule can be a messenger RNA...
s spanning 133kb encoding a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
of 2039 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s and has a predicted molecular weight of 220 kDa. Large insertion
Insertion (genetics)
In genetics, an insertion is the addition of one or more nucleotide base pairs into a DNA sequence. This can often happen in microsatellite regions due to the DNA polymerase slipping...
s and deletion
Deletion
Deletion is the act of deleting or removal by striking out material, such as a word or passage, that has been removed from a body of written or printed matter.Deletion may refer to:*File deletion, a way of removing a file from a computer's file system...
s have given rise to four structurally variant gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s and some alleles may extend up to 160 kb and 9 additional exons. The transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
start site has been mapped to 111 bp upstream of the translation
Translation
Translation is the communication of the meaning of a source-language text by means of an equivalent target-language text. Whereas interpreting undoubtedly antedates writing, translation began only after the appearance of written literature; there exist partial translations of the Sumerian Epic of...
initiation codon ATG and there is another possible start site 29 bp further upstream. The promoter region lacks a distinct TATA box
TATA box
The TATA box is a DNA sequence found in the promoter region of genes in archaea and eukaryotes; approximately 24% of human genes contain a TATA box within the core promoter....
sequence. The gene is expressed principally on erythrocytes, monocytes, neutrophils and B cells but is also present on some T lymphocytes, mast cells and glomerular podocytes.
The mean number of complement receptor 1 (CR1) molecules on erythrocytes in normal individuals lies within the range of 100-1000 molecules per cell. Two codominant allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s exist - one controlling high and the other low expression. Homozygote
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
s differ by a factor of 10-20: heterozygotes
Zygosity
Zygosity refers to the similarity of alleles for a trait in an organism. If both alleles are the same, the organism is homozygous for the trait. If both alleles are different, the organism is heterozygous for that trait...
typically have 500-600 copies per erythrocyte. These two alleles appear to have originated before the divergence of the European and African populations.
Structure
The encoded protein has a 47 amino acid signal peptideSignal peptide
A signal peptide is a short peptide chain that directs the transport of a protein.Signal peptides may also be called targeting signals, signal sequences, transit peptides, or localization signals....
, an extracellular domain of 1930 residues, a 25 residue transmembrane domain and a 43 amino acid C terminal cytoplasmic region. The leader sequence and 5'-untranslated region
Five prime untranslated region
A messenger ribonucleic acid molecule codes for a protein through translation. The mRNA also contains regions that are not translated: in eukaryotes these include the 5' untranslated region, 3' untranslated region, 5' cap and poly-A tail....
are contained in one exon. The large extracellular domain of CR1, which has 25 potential N-glycosylation sites, can be divided into 30 short consensus repeats (SCRs) (also known as complement control protein
Complement control protein
The complement system distinguishes "self" from "non-self" via a range of specialized cell-surface and soluble proteins. These homologous proteins belong to a family called the "regulators of complement activation " or "complement control proteins "...
repeats (CCPs) or sushi domains), each having 60 to 70 amino acids. The sequence homology between SCRs ranges between 60 to 99 percent. The transmembrane region is encoded by 2 exons and the cytoplasmic domain and the 3'-untranslated regions are coded for by two separate exons.
The 30 or so SCRs are further grouped into four longer regions termed long homologous repeats (LHRs) each encoding approximately 45 kDa of protein and designated LHR-A, -B, -C, and -D. The first three have seven SCRs while LHR-D has 9 or more. Each LHR is composed of 8 exons and within an LHR, SCR 1, 5, and 7 are each encoded by a single exon, SCR 2 and 6 are each encoded by 2 exons, and a single exon codes for SCR 3 and 4. The LHR seem to have arisen as a result of unequal crossing over and the event that gave rise to LHR-B seems to have occurred within the fourth exon of either LHR-A or –C. To date the atomic structure have been solved for SCRs 15-16, 16 & 16-17.
Alleles
Four alleles are known with predicted protein molecular weights of 190 kDa, 220 kDa, 250 kDa and 280kDa are known. Multiple size variants (55kDa-220kDa) are also found among non-human primatePrimate
A primate is a mammal of the order Primates , which contains prosimians and simians. Primates arose from ancestors that lived in the trees of tropical forests; many primate characteristics represent adaptations to life in this challenging three-dimensional environment...
s and a partial amino-terminal duplication (CR1-like gene) that encodes the short (55kDa-70kDa) forms expressed on non human erythrocytes. These short CR1 forms, some of which are glycosylphosphatidylinositol (GPI) anchored, are expressed on erythrocytes and the 220kDa molecular weight CR1 form is expressed on monocytes. The gene including the repeats is highly conserved in primates possibly because of the ability of the repeats to bind complement. LHR-A binds preferentially to the complement component C4b: LHR-B and LHR-C bind to C3b and also, albeit with a lower affinity, to C4b. Curiously the human CR1 gene appears to have an unusual protein conformation but the significance of this finding is not clear.
Rosetting
Plasmodium falciparumPlasmodium falciparum
Plasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female Anopheles mosquito. Malaria caused by this species is the most dangerous form of malaria, with the highest rates of complications and mortality...
erythrocyte membrane protein 1 (PfEMP1) interacts with uninfected erythrocytes. This 'stickiness', known as rosetting, is believed to be a strategy used by the parasite to remain sequestered in the microvasculature to avoid destruction in the spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
and liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
. Erythrocyte rosetting causes obstruction of the blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
flow in microcapillaries. There is a direct interaction between PfEMP1 and a functional site of complement receptor type 1 on uninfected erythrocytes.
Role in blood Groups
The Knops antigen was the 25th blood group system recognized and consists of the single antigenAntigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
York
York
York is a walled city, situated at the confluence of the Rivers Ouse and Foss in North Yorkshire, England. The city has a rich heritage and has provided the backdrop to major political events throughout much of its two millennia of existence...
(Yk) a with the following allelic pairs:
- Knops (Kn) a and b
- McCoyMcCoy-People:*McCoy Tyner , American jazz pianist* For people with surname McCoy, see McCoy .-Places:*McCoy Mountains in southern California*Fort McCoy, Florida, an unincorporated community in Florida...
(McC) a and b - Swain-Langley (Sl) 1 and 2
The antigen is known to lie within the CR1 protein repeats and was first described in 1970 in a 37-year-old Caucasian woman. Racial differences exist in the frequency of these antigens: 98.5% and 96.7% of American
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
Caucasians and Africa
Africa
Africa is the world's second largest and second most populous continent, after Asia. At about 30.2 million km² including adjacent islands, it covers 6% of the Earth's total surface area and 20.4% of the total land area...
ns respectively are positive for McC(a). 36% of a Mali population were Kn(a) and 14% of exhibited the null (or Helgeson) phenotype compared with only 1% in the American population. The frequencies of McC (b) and Sl (2) are higher in Africans compared with Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
ans and while the frequency of McC (b) was similar between Africans from the USA or Mali
Mali
Mali , officially the Republic of Mali , is a landlocked country in Western Africa. Mali borders Algeria on the north, Niger on the east, Burkina Faso and the Côte d'Ivoire on the south, Guinea on the south-west, and Senegal and Mauritania on the west. Its size is just over 1,240,000 km² with...
, the Sl (b) phenotype is significantly more common in Mali - 39% and 65% respectively. In Gambia the Sl (2)/McC(b) phenotype appears to have been positively selected - presumably due to malaria. 80% of Papua New Guinea
Papua New Guinea
Papua New Guinea , officially the Independent State of Papua New Guinea, is a country in Oceania, occupying the eastern half of the island of New Guinea and numerous offshore islands...
ns have the Helgeson phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
and case control studies suggest this phenotype has a protective effect against severe malaria
Malaria
Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...
.
External links
- Knops blood group system at BGMUTBGMUTThe BGMUT Database documents allelic variations in the genes encoding for human blood group systems. It was set up in 1999 through an initiative of the Human Genome Variation Society . Since 2006, it has been a part of the dbRBC resource of NCBI at the NIH...
Blood Group Antigen Gene Mutation Database at NCBINational Center for Biotechnology InformationThe National Center for Biotechnology Information is part of the United States National Library of Medicine , a branch of the National Institutes of Health. The NCBI is located in Bethesda, Maryland and was founded in 1988 through legislation sponsored by Senator Claude Pepper...
, NIH