Editing Complement receptor 1

{{Short description|Protein found in humans}}
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{{More citations needed|date=August 2008}}
{{Infobox_gene}}

'''Complement receptor type 1''' ('''CR1''') also known as '''C3b/C4b receptor''' or '''CD35''' (cluster of differentiation 35) is a [[protein]] that in humans is encoded by the ''CR1'' [[gene]].<ref name = "entrez_ 1378">{{cite web | title = Entrez Gene: CR1 complement component (3b/4b) receptor 1 (Knops blood group)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1378}}</ref><ref name="pmid1708809">{{cite journal | vauthors = Moulds JM, Nickells MW, Moulds JJ, Brown MC, Atkinson JP | title = The C3b/C4b receptor is recognized by the Knops, McCoy, Swain-langley, and York blood group antisera | journal = The Journal of Experimental Medicine | volume = 173 | issue = 5 | pages = 1159–1163 | date = May 1991 | pmid = 1708809 | pmc = 2118866 | doi = 10.1084/jem.173.5.1159 }}</ref>

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 [[erythrocyte]]s, [[leukocyte]]s, glomerular [[podocyte]]s, [[hyalocytes]], and splenic follicular [[dendritic cell]]s. 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.<ref name = "entrez_ 1378"/>

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 system|complement]] cascade, mediate [[immune adherence]] and [[phagocytosis]] and inhibit both the classic and alternative pathways. The number of CR1 molecules decreases with aging of [[erythrocyte]]s in normal individuals and is also decreased in pathological conditions such as [[systemic lupus erythematosus]] (SLE), [[HIV]] infection, some [[haemolytic anaemia]]s and other conditions featuring [[immune complex]]es.<ref  name="pmid19004497 ">{{cite journal | vauthors = Khera R, Das N | title = Complement Receptor 1: disease associations and therapeutic implications | journal = Molecular Immunology | volume = 46 | issue = 5 | pages = 761–772 | date = February 2009 | pmid = 19004497 | pmc = 7125513 | doi = 10.1016/j.molimm.2008.09.026 }}</ref>  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]].<ref name="pmid19734903">{{cite journal | vauthors = Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D, Bullido MJ, Tavernier B, Letenneur L, Bettens K, Berr C, Pasquier F, Fiévet N, Barberger-Gateau P, Engelborghs S, De Deyn P, Mateo I, Franck A, Helisalmi S, Porcellini E, Hanon O, de Pancorbo MM, Lendon C, Dufouil C, Jaillard C, Leveillard T, Alvarez V, Bosco P, Mancuso M, Panza F, Nacmias B, Bossù P, Piccardi P, Annoni G, Seripa D, Galimberti D, Hannequin D, Licastro F, Soininen H, Ritchie K, Blanché H, Dartigues JF, Tzourio C, Gut I, Van Broeckhoven C, Alpérovitch A, Lathrop M, Amouyel P | title = Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease | journal = Nature Genetics | volume = 41 | issue = 10 | pages = 1094–1099 | date = October 2009 | pmid = 19734903 | doi = 10.1038/ng.439 | hdl-access = free | s2cid = 24530130 | hdl = 10281/9031 }}
* {{cite magazine |author=Alice Park |date=2009-09-07 |title=Breakthrough Discoveries of Alzheimer's Genes |magazine=[[Time (magazine)|Time]] |url=http://www.time.com/time/health/article/0,8599,1920745,00.html |archive-url=https://web.archive.org/web/20090909142224/http://www.time.com/time/health/article/0,8599,1920745,00.html |archive-date=2009-09-09}}</ref><ref>{{cite journal | vauthors = Fonseca MI, Chu S, Pierce AL, Brubaker WD, Hauhart RE, Mastroeni D, Clarke EV, Rogers J, Atkinson JP, Tenner AJ | title = Analysis of the Putative Role of CR1 in Alzheimer's Disease: Genetic Association, Expression and Function | journal = PLOS ONE | volume = 11 | issue = 2 | pages = e0149792 | year = 2016 | pmid = 26914463 | pmc = 4767815 | doi = 10.1371/journal.pone.0149792 | doi-access = free | bibcode = 2016PLoSO..1149792F }}</ref>

==Gene region==
In humans, the ''CR1'' gene is located 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 [[glycoprotein]] 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]], another immunoregulatory protein, also maps to this location.<ref>{{cite book | vauthors = Das N, Biswas B, Khera R | title = Advances in Experimental Medicine and Biology | volume = 735 | pages = 55–81 | date = 2013 | pmid = 23402019 | doi = 10.1007/978-1-4614-4118-2_4 | chapter = Membrane-Bound Complement Regulatory Proteins as Biomarkers and Potential Therapeutic Targets for SLE | isbn = 978-1-4614-4117-5  }}</ref>

==Gene structure and isoforms==

The canonical Cr2/CD21 gene of subprimate mammals produces two types of complement receptor (CR1, ca. 200 kDa; CR2, ca. 145 kDa) via alternative mRNA splicing. The murine Cr2 gene contains 25 exons; a common first exon is spliced to exon 2 and to exon 9 in transcripts encoding CR1 and CR2, respectively. A transcript with an [[open reading frame]] of 4,224 nucleotides encodes the long isoform, CR1; this is predicted to be a protein of 1,408 amino acids that includes 21 short consensus repeats (SCR) of ca. 60 amino acids each, plus transmembrane and cytoplasmic regions. Isoform CR2 (1,032 amino acids) is encoded by a shorter transcript (3,096 coding nucleotides) that lacks exons 2–8 encoding SCR1-6. CR1 and CR2 on murine B cells form complexes with a co-accessory activation complex containing CD19, CD81, and the fragilis/Ifitm (murine equivalents of LEU13) proteins.<ref name=pmid18713965>{{cite journal | vauthors = Jacobson AC, Weis JH | title = Comparative functional evolution of human and mouse CR1 and CR2 | journal = Journal of Immunology | volume = 181 | issue = 5 | pages = 2953–2959 | date = September 2008 | pmid = 18713965 | pmc = 3366432 | doi = 10.4049/jimmunol.181.5.2953 }}</ref>

The [[complement receptor 2]] (CR2) gene of primates produces only the smaller isoform, CR2; primate CR1, which recapitulates many of the structural domains and presumed functions of Cr2-derived CR1 in subprimates, is encoded by a distinct CR1 gene (apparently derived from the gene Crry of subprimates).

Isoforms CR1 and CR2 derived from the Cr2 gene possess the same C-terminal sequence, such that association with and activation through CD19 should be equivalent. CR1 can bind to C4b and C3b complexes, whereas CR2 (murine and human) binds to C3dg-bound complexes. CR1, a surface protein produced primarily by [[follicular dendritic cell]]s, appears to be critical for generation of appropriately activated B cells of the germinal centre and for mature antibody responses to bacterial infection.<ref name=pmid23733878>{{cite journal | vauthors = Donius LR, Handy JM, Weis JJ, Weis JH | title = Optimal germinal center B cell activation and T-dependent antibody responses require expression of the mouse complement receptor Cr1 | journal = Journal of Immunology | volume = 191 | issue = 1 | pages = 434–447 | date = July 2013 | pmid = 23733878 | pmc = 3707406 | doi = 10.4049/jimmunol.1203176 }}</ref>

The most common allelic variant of the human CR1 gene (CR1*1) is composed of 38 [[exon]]s spanning 133kb encoding a [[protein]] of 2,039 [[amino acid]]s with a predicted molecular weight of 220 kDa. Large [[insertion (genetics)|insertion]]s and [[deletion (genetics)|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 (genetics)|transcription]] start site has been mapped to 111 bp upstream of the [[Translation (biology)|translation]] initiation codon ATG and there is another possible start site 29 bp further upstream. The [[Promoter (biology)|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]].

== Structure ==
The encoded protein has a 47 amino acid [[signal peptide]], an extracellular domain of 1930 residues, a 25 residue transmembrane domain and a 43 amino acid C terminal cytoplasmic region. The [[Five prime untranslated region|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 and 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 known human alleles encode proteins with predicted molecular weights of 190 kDa, 220 kDa, 250 kDa and 280 kDa.<ref name=pmid19004497 /> Multiple size variants (55–220 kDa) are also found among non-human [[primate]]s and a partial amino-terminal duplication (CR1-like gene) that encodes the short (55–70 kDa) forms expressed on non human erythrocytes. These short CR1 forms, some of which are [[glycosylphosphatidylinositol]] (GPI) anchored, are expressed on erythrocytes and the 220-kDa 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.

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. [[Zygosity|Homozygote]]s differ by a factor of 10–20: [[Zygosity|heterozygotes]] typically have 500–600 copies per erythrocyte. These two alleles appear to have originated before the divergence of the European and African populations.

==Rosetting==
[[Plasmodium falciparum erythrocyte membrane protein 1|''Plasmodium falciparum'' 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 [[Microcirculation|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.<ref name=pmid19004497 />

==Role in blood groups==
The [[Knops antigen]] was the 25th blood group system recognized and consists of the single [[antigen]] [[York]] (Yk) a with the following allelic pairs:
* Knops (Kn) a and b
* [[McCoy (allelic pair)|McCoy]] (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 [[whites|Caucasian]] woman. Racial differences exist in the frequency of these antigens: 98.5% and 96.7% of [[United States|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 United States 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]].

== References ==
{{reflist|30em}}

== Further reading ==
{{refbegin | 2}}
* {{cite book |vauthors=Ahearn JM, Fearon DT | chapter = Structure and Function of the Complement Receptors, CR1 (CD35) and CR2 (CD21) | title = Advances in Immunology Volume 46 | volume = 46 | pages = 183–219 | year = 1989 | pmid = 2551147 | doi = 10.1016/S0065-2776(08)60654-9 | isbn = 9780120224463 }}
* {{cite journal | vauthors = Wong WW, Farrell SA | title = Proposed structure of the F' allotype of human CR1. Loss of a C3b binding site may be associated with altered function | journal = Journal of Immunology | volume = 146 | issue = 2 | pages = 656–662 | date = January 1991 | pmid = 1670949 | doi = 10.4049/jimmunol.146.2.656 | s2cid = 22390541 | doi-access = free }}
* {{cite journal | vauthors = Tuveson DA, Ahearn JM, Matsumoto AK, Fearon DT | title = Molecular interactions of complement receptors on B lymphocytes: a CR1/CR2 complex distinct from the CR2/CD19 complex | journal = The Journal of Experimental Medicine | volume = 173 | issue = 5 | pages = 1083–1089 | date = May 1991 | pmid = 1708808 | pmc = 2118840 | doi = 10.1084/jem.173.5.1083 }}
* {{cite journal | vauthors = Moulds JM, Nickells MW, Moulds JJ, Brown MC, Atkinson JP | title = The C3b/C4b receptor is recognized by the Knops, McCoy, Swain-langley, and York blood group antisera | journal = The Journal of Experimental Medicine | volume = 173 | issue = 5 | pages = 1159–1163 | date = May 1991 | pmid = 1708809 | pmc = 2118866 | doi = 10.1084/jem.173.5.1159 }}
* {{cite journal | vauthors = Rao N, Ferguson DJ, Lee SF, Telen MJ | title = Identification of human erythrocyte blood group antigens on the C3b/C4b receptor | journal = Journal of Immunology | volume = 146 | issue = 10 | pages = 3502–3507 | date = May 1991 | pmid = 1827486 | doi = 10.4049/jimmunol.146.10.3502 | s2cid = 31768300 | doi-access = free }}
* {{cite journal | vauthors = Hourcade D, Miesner DR, Bee C, Zeldes W, Atkinson JP | title = Duplication and divergence of the amino-terminal coding region of the complement receptor 1 (CR1) gene. An example of concerted (horizontal) evolution within a gene | journal = The Journal of Biological Chemistry | volume = 265 | issue = 2 | pages = 974–980 | date = January 1990 | pmid = 2295627 | doi = 10.1016/S0021-9258(19)40145-2 | doi-access = free }}
* {{cite journal | vauthors = Reynes M, Aubert JP, Cohen JH, Audouin J, Tricottet V, Diebold J, Kazatchkine MD | title = Human follicular dendritic cells express CR1, CR2, and CR3 complement receptor antigens | journal = Journal of Immunology | volume = 135 | issue = 4 | pages = 2687–2694 | date = October 1985 | pmid = 2411809 | doi = 10.4049/jimmunol.135.4.2687 | s2cid = 46708324 | doi-access = free }}
* {{cite journal | vauthors = Hinglais N, Kazatchkine MD, Mandet C, Appay MD, Bariety J | title = Human liver Kupffer cells express CR1, CR3, and CR4 complement receptor antigens. An immunohistochemical study | journal = Laboratory Investigation; A Journal of Technical Methods and Pathology | volume = 61 | issue = 5 | pages = 509–514 | date = November 1989 | pmid = 2478758 }}
* {{cite journal | vauthors = Fearon DT, Klickstein LB, Wong WW, Wilson JG, Moore FD, Weis JJ, Weis JH, Jack RM, Carter RH, Ahearn JA | title = Immunoregulatory functions of complement: structural and functional studies of complement receptor type 1 (CR1; CD35) and type 2 (CR2; CD21) | journal = Progress in Clinical and Biological Research | volume = 297 | pages = 211–220 | year = 1989 | pmid = 2531419 }}
* {{cite journal | vauthors = Wong WW, Cahill JM, Rosen MD, Kennedy CA, Bonaccio ET, Morris MJ, Wilson JG, Klickstein LB, Fearon DT | title = Structure of the human CR1 gene. Molecular basis of the structural and quantitative polymorphisms and identification of a new CR1-like allele | journal = The Journal of Experimental Medicine | volume = 169 | issue = 3 | pages = 847–863 | date = March 1989 | pmid = 2564414 | pmc = 2189269 | doi = 10.1084/jem.169.3.847 }}
* {{cite journal | vauthors = Wong WW, Kennedy CA, Bonaccio ET, Wilson JG, Klickstein LB, Weis JH, Fearon DT | title = Analysis of multiple restriction fragment length polymorphisms of the gene for the human complement receptor type I. Duplication of genomic sequences occurs in association with a high molecular mass receptor allotype | journal = The Journal of Experimental Medicine | volume = 164 | issue = 5 | pages = 1531–1546 | date = November 1986 | pmid = 2877046 | pmc = 2188435 | doi = 10.1084/jem.164.5.1531 }}
* {{cite journal | vauthors = Wong WW, Klickstein LB, Smith JA, Weis JH, Fearon DT | title = Identification of a partial cDNA clone for the human receptor for complement fragments C3b/C4b | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 82 | issue = 22 | pages = 7711–7715 | date = November 1985 | pmid = 2933745 | pmc = 391403 | doi = 10.1073/pnas.82.22.7711 | doi-access = free | bibcode = 1985PNAS...82.7711W }}
* {{cite journal | vauthors = Klickstein LB, Wong WW, Smith JA, Weis JH, Wilson JG, Fearon DT | title = Human C3b/C4b receptor (CR1). Demonstration of long homologous repeating domains that are composed of the short consensus repeats characteristics of C3/C4 binding proteins | journal = The Journal of Experimental Medicine | volume = 165 | issue = 4 | pages = 1095–1112 | date = April 1987 | pmid = 2951479 | pmc = 2188588 | doi = 10.1084/jem.165.4.1095 }}
* {{cite journal | vauthors = Moldenhauer F, David J, Fielder AH, Lachmann PJ, Walport MJ | title = Inherited deficiency of erythrocyte complement receptor type 1 does not cause susceptibility to systemic lupus erythematosus | journal = Arthritis and Rheumatism | volume = 30 | issue = 9 | pages = 961–966 | date = September 1987 | pmid = 2959289 | doi = 10.1002/art.1780300901 | doi-access =  }}
* {{cite journal | vauthors = Hourcade D, Miesner DR, Atkinson JP, Holers VM | title = Identification of an alternative polyadenylation site in the human C3b/C4b receptor (complement receptor type 1) transcriptional unit and prediction of a secreted form of complement receptor type 1 | journal = The Journal of Experimental Medicine | volume = 168 | issue = 4 | pages = 1255–1270 | date = October 1988 | pmid = 2971757 | pmc = 2189081 | doi = 10.1084/jem.168.4.1255 }}
* {{cite journal | vauthors = Klickstein LB, Bartow TJ, Miletic V, Rabson LD, Smith JA, Fearon DT | title = Identification of distinct C3b and C4b recognition sites in the human C3b/C4b receptor (CR1, CD35) by deletion mutagenesis | journal = The Journal of Experimental Medicine | volume = 168 | issue = 5 | pages = 1699–1717 | date = November 1988 | pmid = 2972794 | pmc = 2189104 | doi = 10.1084/jem.168.5.1699 }}
* {{cite journal | vauthors = Hing S, Day AJ, Linton SJ, Ripoche J, Sim RB, Reid KB, Solomon E | title = Assignment of complement components C4 binding protein (C4BP) and factor H (FH) to human chromosome 1q, using cDNA probes | journal = Annals of Human Genetics | volume = 52 | issue = 2 | pages = 117–122 | date = May 1988 | pmid = 2977721 | doi = 10.1111/j.1469-1809.1988.tb01086.x | s2cid = 37855701 }}
* {{cite journal | vauthors = Fearon DT | title = Human complement receptors for C3b (CR1) and C3d (CR2) | journal = The Journal of Investigative Dermatology | volume = 85 | issue = 1 Suppl | pages = 53s–57s | date = July 1985 | pmid = 2989379 | doi = 10.1111/1523-1747.ep12275473 | doi-access = free }}
* {{cite journal | vauthors = Wilson JG, Murphy EE, Wong WW, Klickstein LB, Weis JH, Fearon DT | title = Identification of a restriction fragment length polymorphism by a CR1 cDNA that correlates with the number of CR1 on erythrocytes | journal = The Journal of Experimental Medicine | volume = 164 | issue = 1 | pages = 50–59 | date = July 1986 | pmid = 3014040 | pmc = 2188187 | doi = 10.1084/jem.164.1.50 }}
{{refend}}

== External links ==
* {{MeshName|CR1+protein,+human}}
* {{MeshName|Receptors,+Complement+3b}}
* [https://www.ncbi.nlm.nih.gov/projects/mhc/xslcgi.fcgi?cmd=bgmut/systems_info&system=knops Knops blood group system] at [[BGMUT]] Blood Group Antigen Gene Mutation Database at [[National Center for Biotechnology Information|NCBI]], [[NIH]]

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{{Clusters of differentiation}}
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[[Category:Complement system]]
[[Category:Clusters of differentiation]]
[[Category:Transfusion medicine]]
[[Category:Blood antigen systems]]