Complement receptor 1

Source: Wikipedia, the free encyclopedia.
CR1
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
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 Mbn/a
PubMed search[2]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.[3][4]

This gene is a member of the

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.[3]

In primates, CR1 serves as the main system for processing and clearance of complement

haemolytic anaemias and other conditions featuring immune complexes.[5]
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.[6][7]

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.

Factor H, another immunoregulatory protein, also maps to this location.[8]

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.[9]

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.[10]

The most common allelic variant of the human CR1 gene (CR1*1) is composed of 38

glomerular podocytes
.

Structure

The encoded protein has a 47 amino acid

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.[5] 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

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.[5]

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:

The antigen is known to lie within the CR1 protein repeats and was first described in 1970 in a 37-year-old

case–control studies suggest this phenotype has a protective effect against severe malaria
.

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000203710 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ a b "Entrez Gene: CR1 complement component (3b/4b) receptor 1 (Knops blood group)".
  4. PMID 1708809
    .
  5. ^
    PMID 19004497
    .
  6. S2CID 24530130
    .
  7. PMID 26914463
    .
  8. PMID 23402019
    .
  9. PMID 18713965
    .
  10. PMID 23733878
    .

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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