Complement receptor type 1 (CR1)

The protein contains 2039 amino acids for an estimated molecular weight of 223663 Da.

 

Membrane immune adherence receptor that plays a critical role in the capture and clearance of complement-opsonized pathogens by erythrocytes and monocytes/macrophages (PubMed:2963069). Mediates the binding by these cells of particles and immune complexes that have activated complement to eliminate them from the circulation (PubMed:2963069). Acts also in the inhibition of spontaneous complement activation by impairing the formation and function of the alternative and classical pathway C3/C5 convertases, and by serving as a cofactor for the cleavage by factor I of C3b to iC3b, C3c and C3d,g, and of C4b to C4c and C4d (PubMed:2972794, PubMed:8175757). Plays also a role in immune regulation by contributing, upon ligand binding, to the generation of regulatory T cells from activated helper T cells (PubMed:25742728).', '(Microbial infection) Acts as a receptor for Epstein-Barr virus. (updated: Dec. 5, 2018)

Protein identification was indicated in the following studies:

  1. Goodman and co-workers. (2013) The proteomics and interactomics of human erythrocytes. Exp Biol Med (Maywood) 238(5), 509-518.
  2. Lange and co-workers. (2014) Annotating N termini for the human proteome project: N termini and Nα-acetylation status differentiate stable cleaved protein species from degradation remnants in the human erythrocyte proteome. J Proteome Res. 13(4), 2028-2044.
  3. Hegedűs and co-workers. (2015) Inconsistencies in the red blood cell membrane proteome analysis: generation of a database for research and diagnostic applications. Database (Oxford) 1-8.
  4. Bryk and co-workers. (2017) Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res. 16(8), 2752-2761.
  5. D'Alessandro and co-workers. (2017) Red blood cell proteomics update: is there more to discover? Blood Transfus. 15(2), 182-187.
  6. Chu and co-workers. (2018) Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation. Br J Haematol. 180(1), 118-133.

Methods

The following articles were analysed to gather the proteome content of erythrocytes.

The gene or protein list provided in the studies were processed using the ID mapping API of Uniprot in September 2018. The number of proteins identified and mapped without ambiguity in these studies is indicated below.
Only Swiss-Prot entries (reviewed) were considered for protein evidence assignation.

PublicationIdentification 1Uniprot mapping 2Not mapped /
Obsolete		TrEMBLSwiss-Prot
Goodman (2013)2289 (gene list)227853205992269
Lange (2014)123412347281224
Hegedus (2015)2638262202352387
Wilson (2016)165815281702911068
d'Alessandro (2017)18261817201815
Bryk (2017)20902060101081942
Chu (2018)18531804553621387

1 as available in the article and/or in supplementary material
2 uniprot mapping returns all protein isoforms as one entry

The compilation of older studies can be retrieved from the Red Blood Cell Collection database.

The data and differentiation stages presented below come from the proteomic study and analysis performed by our partners of the GReX consortium, more details are available in their published work.

No sequence conservation computed yet.
Protein sequence (FASTA)
Protein coevolution profile (FreeContact)
Multiple Sequence Alignment (Muscle)

This protein is annotated as membranous in Gene Ontology, is predicted to be membranous by TOPCONS.

Topcons

Interpro domains
Total structural coverage: 97%
Model score: 100
MODL_ROSETTA-3.4

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VariantDescription
dbSNP:rs2274567
empty
dbSNP:rs3737002
dbSNP:rs17259045
MCC(b) antigen
Sl(2)/Vil antigen and Sl(3) antigen
Sl(3) antigen
dbSNP:rs6691117
dbSNP:rs3811381
empty
dbSNP:rs2296160

Biological Process

ATP export GO Logo
Complement activation, alternative pathway GO Logo
Complement activation, classical pathway GO Logo
Complement receptor mediated signaling pathway GO Logo
Immune complex clearance by erythrocytes GO Logo
Innate immune response GO Logo
Negative regulation of activation of membrane attack complex GO Logo
Negative regulation of complement activation GO Logo
Negative regulation of complement activation, alternative pathway GO Logo
Negative regulation of complement activation, classical pathway GO Logo
Negative regulation of cytolysis GO Logo
Negative regulation of immunoglobulin production GO Logo
Negative regulation of interferon-gamma production GO Logo
Negative regulation of interleukin-2 production GO Logo
Negative regulation of plasma cell differentiation GO Logo
Negative regulation of serine-type endopeptidase activity GO Logo
Negative regulation of T cell proliferation GO Logo
Neutrophil degranulation GO Logo
Plasma membrane organization GO Logo
Positive regulation of activation of membrane attack complex GO Logo
Positive regulation of cell population proliferation GO Logo
Positive regulation of regulatory T cell differentiation GO Logo
Positive regulation of serine-type endopeptidase activity GO Logo
Regulation of complement activation GO Logo
Regulation of regulatory T cell differentiation GO Logo

Cellular Component

Cell surface GO Logo
Cytoskeleton GO Logo
Extracellular exosome GO Logo
Ficolin-1-rich granule membrane GO Logo
Integral component of plasma membrane GO Logo
Plasma membrane GO Logo
Plasma membrane raft GO Logo
Secretory granule membrane GO Logo

Molecular Function

Complement component C3b binding GO Logo
Complement component C3b receptor activity GO Logo
Complement component C4b binding GO Logo
Complement component C4b receptor activity GO Logo
Virus receptor activity GO Logo

The reference OMIM entry for this protein is 120620

Complement component receptor 1; cr1
Complement component 3b/4b receptor
C3-binding protein
C3br
C4br
Cd35

DESCRIPTION

CR1 is a multiple modular protein that binds C3b (120700)/C4b (120820)-opsonized foreign antigens. By doing so, CR1 mediates the immune adherence phenomenon, a fundamental event for destroying microbes and initiating an immunologic response (Smith et al., 2002).

MAPPING

Although C3BR was assigned to chromosome 6 by somatic cell hybrid studies (Curry et al., 1976), the immunoelectrophoretic polymorphism does not show linkage to HLA. Atkinson (1983) counseled caution in interpretation of the studies of Curry et al. (1976) because the ligands used were no longer considered acceptable reagents for identifying the receptors, the C3bi receptor (unknown in 1976) may account for all or part of the rosette data, and the Raji cell does not have the CR1 C3b/C4b receptor. Rodriguez de Cordoba et al. (1985) concluded that factor H (HF; 134370), C4BP (120830), C3BR, and C3DR (CR2; 120650) represent a linked cluster of genes for proteins regulating the activation of C3. They called the cluster RCA for regulators of complement activation. They showed, furthermore, that RCA segregates independently of HLA, the C2, C4, Bf cluster (on 6p), and C3 (on 19p). Weis et al. (1987) mapped both CR1 and CR2 to chromosome 1q32 by use of partial cDNA clones in in situ hybridization and in Southern analysis of DNA from somatic cell hybrids. Using cDNA probes, Hing et al. (1988) assigned the genes for HF and C3-binding protein to chromosome 1q. Weis et al. (1987) indicated that C3b receptor is the same as C4b receptor (see 120830); it may be, however, that the 2 are closely related proteins determined by closely linked genes on chromosome 1.

BIOCHEMICAL FEATURES

Smith et al. (2002) reported the structure of the principal C3b/C4b-binding site (residues 901 to 1,095) of CR1, which revealed 3 complement control protein modules (modules 15 to 17) in an extended head-to-tail arrangement, with flexibility at the 16-17 junction. Structure-guided mutagenesis identified a positively charged surface region on module 15 that is critical for C4b binding.

GENE FUNCTION

In studying Treponema pallidum, Nelson (1953) observed a phenomenon he called immune adherence. Immune adherence is the specific attachment of primate red cells to antigen-antibody complexes in the presence of complement and involves the binding of complement-fixing immune complexes to the immune-adherence receptor, CR1, normally present on human red cells. CR2 is part of an activating signal complex with CD19 (107265) and CD81 (186845) that transduces a positive signal upon coligation with surface IgM on B cells. Jozsi et al. (2002) showed that aggregated C3, mimicking multimeric C3b, strongly binds to CR1 and inhibits, in a dose-dependent manner, the anti-IgM-induced tyrosine phosphorylation of cytoplasmic proteins, intracellular calcium increase, and proliferation of B lymphocytes. This inhibitory activity occurred even in the presence of IL2 (147680) and IL15 (600554). Jozsi et al. (2002) concluded that CR1 plays a role opposite that of CR2 in the regulation of B-cell activation. Plasmodium falciparum is responsible for the most severe form of malaria (see 611162) in humans. By incubating erythrocytes with increasing amounts of anti-CR1 antibodies or soluble CR1, followed by immunoprecipitation analysis, Tham et al. (2010) showed that the P. falciparum merozoite ligand PfRh4 bound to CR1. Levels of PfRh4 binding correlated with CR1 expression on the erythro ... More on the omim web site

The reference OMIM entry for this protein is 607486

Knops blood group system; kn

A number sign (#) is used with this entry because the Knops blood group system represents antigens carried by complement receptor-1 (CR1; 120620) of the erythrocyte cell membrane. The Knops blood group system comprises 5 high-incidence antigens designated KN1-KN5 (Daniels, 1995). The Knops system antigens are carried on complement receptor-1. In humans, 4 CR1 allotypes of different size are known and all of them express the Knops system antigens. The extracellular domain of CR1, which has 25 potential N-glycosylation sites, can be divided into 30 short consensus repeats (SCRs), each having 60 to 70 amino acids with sequence homology between SCRs ranging from 60 to 90%. The first 28 SCRs are further arranged into 4 longer regions termed long homologous repeats (LHRs), designated LHR-A, LHR-B, LHR-C, and LHR-D and consisting of 7 SCRs each. Tamasauskas et al. (2001) reported studies indicating that the high-incidence Knops system antigens reside within LHR-D and to a lesser extent within LHR-C. Sl(a) (KN4, or Swain-Langley) is involved in malarial rosetting (Rowe et al., 1997), a process associated with cerebral malaria (see 611162), which is the major cause of mortality from Plasmodium falciparum. Reduction in rosette formation occurred with Sl(a-) RBCs. Because the Sl(a-) phenotype is more common in persons of African ancestry (Daniels, 1995), Moulds and Moulds (2000) suggested that this phenotype provided protection against fatal falciparum malaria. The studies of Tamasauskas et al. (2001) suggested that LHR-D may represent an additional malaria interaction region in CR1. ... More on the omim web site

The reference OMIM entry for this protein is 611162

Malaria, susceptibility to malaria, resistance to, included
Malaria, severe, susceptibility to, included
Malaria, severe, resistance to, included
Malaria, cerebral, susceptibility to, included
Malaria, cerebral, resistance to, included

A number sign (#) is used with this entry because variation in several different genes influences susceptibility and resistance to malaria, as well as disease progression and severity. These genes include HBB (141900), ICAM1 (147840), CD36 (173510), CR1 (120620), GYPA (111300), GYPB (111740), GYPC (110750), TNF (191160), NOS2A (163730), TIRAP (606252), FCGR2B (604590), and CISH (602441). In addition, a locus associated with Plasmodium falciparum blood infection level has been mapped to chromosome 5q31-q33 (PFBI; 248310), a locus for susceptibility to mild malaria has been mapped to chromosome 6p21.3 (MALS; 609148), a locus associated with malaria fever episodes has been mapped to chromosome 10p15 (PFFE1; 611384), and a locus for susceptibility to placental malarial infection has been mapped to chromosome 6 (FUT9; 606865). Complete protection from Plasmodium vivax infection is associated with the Duffy blood group-negative phenotype (see 110700). Alpha(+)-thalassemia (141800), the X-linked disorder G6PD deficiency (300908), and Southeast Asian ovalocytosis (109270) are associated with resistance to malaria.

DESCRIPTION

Malaria, a major cause of child mortality worldwide, is caused by mosquito-borne hematoprotozoan parasites of the genus Plasmodium. Of the 4 species that infect humans, P. falciparum causes the most severe forms of malaria and is the major cause of death and disease. Although less fatal, P. malariae, P. ovale, and, in particular, P. vivax infections are major causes of morbidity. The parasite cycle involves a first stage in liver cells and a subsequent stage at erythrocytes, when malaria symptoms occur. A wide spectrum of phenotypes are observed, from asymptomatic infection to mild disease, including fever and mild anemia, to severe disease, including cerebral malaria, profound anemia, and respiratory distress. Genetic factors influence the response to infection, as well as disease progression and severity. Malaria is the strongest known selective pressure in the recent history of the human genome, and it is the evolutionary driving force behind sickle-cell disease (603903), thalassemia (see 141800), glucose-6-phosphatase deficiency (300908), and other erythrocyte defects that together constitute the most common mendelian diseases of humans (Kwiatkowski, 2005; Campino et al., 2006).

PATHOGENESIS

Compared with other microorganisms, P. falciparum malaria parasites reach very high densities in blood. P. falciparum-infected erythrocytes (PfIRBCs) induce ICAM1 (147840) expression on human brain microvascular endothelial cells (HBMECs), but not on human umbilical vein endothelial cells. PfIRBCs compromise the electrical function of brain endothelium independently of PfIRBC binding phenotype, suggesting a role for soluble parasite factors. By performing genomewide transcriptional profiling of HBMECs after exposure to isogenic PfIRBCs, followed by ELISA for protein identification, Tripathi et al. (2009) identified upregulated molecules involved in immune response, apoptosis and antiapoptosis, inflammatory response, cell-cell signaling, and signal transduction and activation of the NF-kappa-B (see 164011) cascade. Proinflammatory molecules, including CCL20 (601960), CXCL1 (155730), CXCL2 (139110), IL6 (147620), and IL8 (146930), were upregulated more than 100-fold. Tripathi et al. (2009) concluded that PfIRBC exposure to HBMECs results in a predominantly proinflammatory response mediated by NF-kappa-B activati ... More on the omim web site

Subscribe to this protein entry history

July 2, 2021: Protein entry updated
Automatic update: OMIM entry 120620 was added.

July 2, 2021: Protein entry updated
Automatic update: OMIM entry 607486 was added.

July 2, 2021: Protein entry updated
Automatic update: OMIM entry 611162 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 120620 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 607486 was added.

April 11, 2021: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 120620 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 607486 was added.

Feb. 17, 2021: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 120620 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 607486 was added.

Oct. 21, 2020: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 120620 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 607486 was added.

Aug. 25, 2020: Protein entry updated
Automatic update: OMIM entry 611162 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 120620 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 607486 was added.

June 30, 2020: Protein entry updated
Automatic update: OMIM entry 611162 was added.

April 26, 2020: Protein entry updated
Automatic update: OMIM entry 120620 was added.

April 26, 2020: Protein entry updated
Automatic update: OMIM entry 607486 was added.

April 26, 2020: Protein entry updated
Automatic update: OMIM entry 611162 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 120620 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 607486 was added.

March 4, 2020: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 120620 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 607486 was added.

Jan. 23, 2020: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 120620 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 607486 was added.

Dec. 3, 2019: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 120620 was added.

Oct. 28, 2019: Protein entry updated
Automatic update: OMIM entry 607486 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 120620 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 607486 was added.

Sept. 22, 2019: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 120620 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 607486 was added.

Aug. 20, 2019: Protein entry updated
Automatic update: OMIM entry 611162 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 120620 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 607486 was added.

June 7, 2019: Protein entry updated
Automatic update: OMIM entry 611162 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 607486 was added.

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 611162 was added.

May 12, 2019: Protein entry updated
Automatic update: model status changed

May 12, 2019: Protein entry updated
Automatic update: OMIM entry 120620 was added.

Dec. 9, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.

Nov. 17, 2018: Protein entry updated
Automatic update: model status changed

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 120620 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 607486 was added.

Nov. 17, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Oct. 19, 2018: Protein entry updated
Automatic update: OMIM entry 120620 was added.

Oct. 19, 2018: Protein entry updated
Automatic update: OMIM entry 607486 was added.

Oct. 19, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 120620 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 607486 was added.

Oct. 2, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

July 7, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 120620 was added.

July 6, 2018: Protein entry updated
Automatic update: OMIM entry 607486 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 120620 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 607486 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 120620 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 607486 was added.

July 5, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 120620 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 607486 was added.

July 4, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 120620 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 607486 was added.

July 2, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

May 27, 2018: Protein entry updated
Automatic update: OMIM entry 120620 was added.

May 27, 2018: Protein entry updated
Automatic update: OMIM entry 607486 was added.

May 27, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 120620 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 607486 was added.

April 27, 2018: Protein entry updated
Automatic update: OMIM entry 611162 was added.

Feb. 10, 2018: Protein entry updated
Automatic update: Entry updated from uniprot information.

Feb. 2, 2018: Protein entry updated
Automatic update: Uniprot description updated

Dec. 19, 2017: Protein entry updated
Automatic update: Uniprot description updated

Nov. 23, 2017: Protein entry updated
Automatic update: Uniprot description updated

Oct. 26, 2017: Protein entry updated
Automatic update: model status changed

March 25, 2017: Additional information
No protein expression data in P. Mayeux work for CR1

March 16, 2016: Protein entry updated
Automatic update: OMIM entry 120620 was added.

Feb. 24, 2016: Protein entry updated
Automatic update: model status changed

Jan. 28, 2016: Protein entry updated
Automatic update: model status changed

Jan. 24, 2016: Protein entry updated
Automatic update: model status changed