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(Redirected from CD35) Protein found in humans

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CR1

Available structures

PDB

Human UniProt search: PDBe RCSB

List of PDB id codes
1GKG, 1GKN, 1PPQ, 2Q7Z, 2MCY, 2MCZ, 5FO9

Identifiers

Aliases

CR1, C3BR, C4BR, CD35, KN, complement component 3b/4b receptor 1 (Knops blood group), complement C3b/C4b receptor 1 (Knops blood group)

External IDs

OMIM: 120620; HomoloGene: 55474; GeneCards: CR1; OMA:CR1 - orthologs

Gene location (Human)

Chr.	Chromosome 1 (human)

Band	1q32.2	Start	207,496,147 bp
Band	1q32.2	End	207,641,765 bp

RNA expression pattern

Bgee

Human

Mouse (ortholog)

Top expressed in

blood

monocyte

spleen

appendix

lymph node

bone marrow

trabecular bone

granulocyte

superficial temporal artery

bone marrow cells

n/a

More reference expression data

BioGPS


More reference expression data

Gene ontology
Molecular function	virus receptor activity complement component C3b receptor activity complement component C4b receptor activity complement component C3b binding complement component C4b binding
Cellular component	integral component of membrane membrane plasma membrane integral component of plasma membrane cell surface extracellular exosome secretory granule membrane ficolin-1-rich granule membrane
Biological process	negative regulation of complement activation, classical pathway immune system process positive regulation of serine-type endopeptidase activity negative regulation of complement activation, alternative pathway complement activation, classical pathway viral entry into host cell viral process negative regulation of serine-type endopeptidase activity regulation of complement activation complement receptor mediated signaling pathway innate immune response neutrophil degranulation regulation of regulatory T cell differentiation
Sources:Amigo / QuickGO

Orthologs

Species

Human

Mouse

Entrez


1378


n/a

Ensembl


ENSG00000203710


n/a

UniProt


P17927


n/a

RefSeq (mRNA)


NM_000573 NM_000651 NM_001381851


n/a

RefSeq (protein)


NP_000564 NP_000642 NP_001368780


n/a

Location (UCSC)

Chr 1: 207.5 – 207.64 Mb

n/a

PubMed search

n/a

Wikidata

View/Edit Human

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.

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, hyalocytes, 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 haemolytic anaemias and other conditions featuring immune complexes. 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.

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.

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.

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 cells, appears to be critical for generation of appropriately activated B cells of the germinal centre and for mature antibody responses to bacterial infection.

The most common allelic variant of the human CR1 gene (CR1*1) is composed of 38 exons spanning 133kb encoding a protein of 2,039 amino acids with a predicted molecular weight of 220 kDa. Large insertions and deletions have given rise to four structurally variant genes 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.

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 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. Multiple size variants (55–220 kDa) are also found among non-human primates 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 alleles exist – one controlling high and the other low expression. Homozygotes 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.

Rosetting

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 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.

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 (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 Caucasians and Africans 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 Europeans 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 Guineans have the Helgeson phenotype and case–control studies suggest this phenotype has a protective effect against severe malaria.

References

^ GRCh38: Ensembl release 89: ENSG00000203710 – Ensembl, May 2017
"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Entrez Gene: CR1 complement component (3b/4b) receptor 1 (Knops blood group)".
Moulds JM, Nickells MW, Moulds JJ, Brown MC, Atkinson JP (May 1991). "The C3b/C4b receptor is recognized by the Knops, McCoy, Swain-langley, and York blood group antisera". The Journal of Experimental Medicine. 173 (5): 1159–1163. doi:10.1084/jem.173.5.1159. PMC 2118866. PMID 1708809.
^ Khera R, Das N (February 2009). "Complement Receptor 1: disease associations and therapeutic implications". Molecular Immunology. 46 (5): 761–772. doi:10.1016/j.molimm.2008.09.026. PMC 7125513. PMID 19004497.
Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, et al. (October 2009). "Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease". Nature Genetics. 41 (10): 1094–1099. doi:10.1038/ng.439. hdl:10281/9031. PMID 19734903. S2CID 24530130.
- Alice Park (2009-09-07). "Breakthrough Discoveries of Alzheimer's Genes". Time. Archived from the original on 2009-09-09.
Fonseca MI, Chu S, Pierce AL, Brubaker WD, Hauhart RE, Mastroeni D, et al. (2016). "Analysis of the Putative Role of CR1 in Alzheimer's Disease: Genetic Association, Expression and Function". PLOS ONE. 11 (2): e0149792. Bibcode:2016PLoSO..1149792F. doi:10.1371/journal.pone.0149792. PMC 4767815. PMID 26914463.
Das N, Biswas B, Khera R (2013). "Membrane-Bound Complement Regulatory Proteins as Biomarkers and Potential Therapeutic Targets for SLE". Advances in Experimental Medicine and Biology. Vol. 735. pp. 55–81. doi:10.1007/978-1-4614-4118-2_4. ISBN 978-1-4614-4117-5. PMID 23402019.
Jacobson AC, Weis JH (September 2008). "Comparative functional evolution of human and mouse CR1 and CR2". Journal of Immunology. 181 (5): 2953–2959. doi:10.4049/jimmunol.181.5.2953. PMC 3366432. PMID 18713965.
Donius LR, Handy JM, Weis JJ, Weis JH (July 2013). "Optimal germinal center B cell activation and T-dependent antibody responses require expression of the mouse complement receptor Cr1". Journal of Immunology. 191 (1): 434–447. doi:10.4049/jimmunol.1203176. PMC 3707406. PMID 23733878.

External links

CR1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Receptors,+Complement+3b at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Knops blood group system at BGMUT Blood Group Antigen Gene Mutation Database at NCBI, NIH

v t e PDB gallery
1gkg: STRUCTURE DETERMINATION AND RATIONAL MUTAGENESIS REVEAL BINDING SURFACE OF IMMUNE ADHERENCE RECEPTOR, CR1 (CD35) 1gkn: STRUCTURE DETERMINATION AND RATIONAL MUTAGENESIS REVEAL BINDING SURFACE OF IMMUNE ADHERENCE RECEPTOR, CR1 (CD35) 1ppq: NMR structure of 16th module of Immune Adherence Receptor, Cr1 (Cd35)

v t e Proteins: clusters of differentiation (see also list of human clusters of differentiation)
1–50	CD1 a-c 1A 1B 1D 1E CD2 CD3 γ δ ε CD4 CD5 CD6 CD7 CD8 a CD9 CD10 CD11 a b c d CD13 CD14 CD15 CD16 A B CD18 CD19 CD20 CD21 CD22 CD23 CD24 CD25 CD26 CD27 CD28 CD29 CD30 CD31 CD32 A B CD33 CD34 CD35 CD36 CD37 CD38 CD39 CD40 CD41 CD42 a b c d CD43 CD44 CD45 CD46 CD47 CD48 CD49 a b c d e f CD50
51–100	CD51 CD52 CD53 CD54 CD55 CD56 CD57 CD58 CD59 CD61 CD62 E L P CD63 CD64 A B C CD66 a b c d e f CD68 CD69 CD70 CD71 CD72 CD73 CD74 CD78 CD79 a b CD80 CD81 CD82 CD83 CD84 CD85 a d e h j k CD86 CD87 CD88 CD89 CD90 CD91 - CD92 CD93 CD94 CD95 CD96 CD97 CD98 CD99 CD100
101–150	CD101 CD102 CD103 CD104 CD105 CD106 CD107 a b CD108 CD109 CD110 CD111 CD112 CD113 CD114 CD115 CD116 CD117 CD118 CD119 CD120 a b CD121 a b CD122 CD123 CD124 CD125 CD126 CD127 CD129 CD130 CD131 CD132 CD133 CD134 CD135 CD136 CD137 CD138 CD140b CD141 CD142 CD143 CD144 CD146 CD147 CD148 CD150
151–200	CD151 CD152 CD153 CD154 CD155 CD156 a b c CD157 CD158 (a d e i k) CD159 a c CD160 CD161 CD162 CD163 CD164 CD166 CD167 a b CD168 CD169 CD170 CD171 CD172 a b g CD174 CD177 CD178 CD179 a b CD180 CD181 CD182 CD183 CD184 CD185 CD186 CD191 CD192 CD193 CD194 CD195 CD196 CD197 CDw198 CDw199 CD200
201–250	CD201 CD202b CD204 CD205 CD206 CD207 CD208 CD209 CDw210 a b CD212 CD213a 1 2 CD217 CD218 (a b) CD220 CD221 CD222 CD223 CD224 CD225 CD226 CD227 CD228 CD229 CD230 CD233 CD234 CD235 a b CD236 CD238 CD239 CD240CE CD240D CD241 CD243 CD244 CD246 CD247 - CD248 CD249
251–300	CD252 CD253 CD254 CD256 CD257 CD258 CD261 CD262 CD263 CD264 CD265 CD266 CD267 CD268 CD269 CD271 CD272 CD273 CD274 CD275 CD276 CD278 CD279 CD280 CD281 CD282 CD283 CD284 CD286 CD288 CD289 CD290 CD292 CDw293 CD294 CD295 CD297 CD298 CD299
301–350	CD300A CD301 CD302 CD303 CD304 CD305 CD306 CD307 CD309 CD312 CD314 CD315 CD316 CD317 CD318 CD320 CD321 CD322 CD324 CD325 CD326 CD327 CD328 CD329 CD331 CD332 CD333 CD334 CD335 CD336 CD337 CD338 CD339 CD340 CD344 CD349 CD350