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Glycophorin C ( GYPC; CD236/ CD236R; glycoprotein beta; glycoconnectin; PAS-2) plays a functionally important role in maintaining erythrocyte shape and regulating membrane material properties, possibly through its interaction with protein 4.1. Moreover, it has previously been shown that membranes deficient in protein 4.1 exhibit decreased content of glycophorin C. It is also an integral membrane protein of the erythrocyte and acts as the receptor for the Plasmodium falciparum protein PfEBP-2 (erythrocyte binding protein 2; baebl; EBA-140).
Originally it was thought that glycophorin C and D were the result of a gene duplication event but it was only later realised that they were encoded by the same gene. Glycophorin D (GPD) is generated from the glycophorin C messenger RNA by leaky scanning at an in frame AUG at codon 30: glycophorin D = glycophorin C residues 30 to 128. This leaky translation appears to be a uniquely human trait.
Glycophorin C (GPC) is a single polypeptide chain of 128 amino acids and is encoded by a gene on the long arm of chromosome 2 (2q14-q21). The gene was first cloned in 1989 by High et al. The GPC gene is organized in four distributed over 13.5 kilobase pairs of DNA. Exon 1 encodes residues 1-16, exon 2 residues 17-35, exon 3 residues 36-63 and exon 4 residues 64-128. Exons 2 and 3 are highly homologous, with less than 5% nucleotide divergence. These exons also differ by a 9 amino acid insert at the 3' end of exon 3. The direct repeated segments containing these exons is 3.4 kilobase pairs long and may be derived from a recent duplication of a single ancestral domain. Exons 1, 2 and most of exon 3 encode the N-terminal extracellular domain while the remainder of exon 3 and exon 4 encode transmembrane and cytoplasmic domains.
Two are known and the gene is expressed in a wide variety of tissues including kidney, thymus, stomach, breast, adult liver and erythrocyte. In the non erythroid cell lines, expression is lower than in the erythrocyte and the protein is differentially glycosylation. In the erythrocyte glycophorin C makes up ~4% of the membrane sialoglycoproteins. The average number of O linked chains is 12 per molecule.
The gene is expressed early in the development of the erythrocyte, specifically in the erythroid burst-forming unit and erythroid colony-forming unit. The mRNA from human erythroblasts is ~1.4 kilobases long and the transcription start site in erythroid cells has been mapped to 1050 base pairs 5' of the start codon. It is expressed early in development and before the , RHAG, glycophorin A, band 3, the Rhesus antigen and glycophorin B.
In melanocytic cells Glycophorin C gene expression may be regulated by MITF.
GPC appears to be synthesized in excess in the erythrocyte and that the membrane content is regulated by band 4.1 (protein 4.1). Additional data on the regulation of glycophorin C is here.
In a study of this gene among the Hominoidea two finding unique to humans emerged: (1) an excess of non-synonymous divergence among species that appears to be caused solely by accelerated evolution and (2) the ability of the single GYPC gene to encode both the GPC and GPD proteins. The cause for this is not known but it was suggested that these findings might be the result of infection by Plasmodium falciparum.
Glycophorin C was first isolated in 1978. Glycophorin C and D are minor sialoglycoproteins contributing to 4% and 1% to the PAS-positive material and are present at about 2.0 and 0.5 x 105 copies/cell respectively. In polyacrylimide gels glycophorin C's apparent weight is 32 kilodaltons (32 kDa). Its structure is similar to that of other glycophorins: a highly glycoslated extracellular domain (residues 1-58), a transmembrane domain (residues 59-81) and an intracellular domain (residues 82-128). About 90% of the glycophorin C present in the erythrocyte is bound to the cytoskeleton and the remaining 10% moves freely within the membrane.
Glycophorin D's apparent molecular weight is 23kDa. On average this protein has 6 O linked oligosaccharides per molecule.
Within the erythrocyte it interacts with band 4.1 (an 80-kDa protein) and p55 (a palmitoylation peripheral membrane phosphoprotein and a member of the membrane-associated guanylate kinase family) to form a ternary complex that is critical for the shape and stability of erythrocytes. The major attachment sites between the erythrocyte spectrin-actin cytoskeleton and the lipid bilayer are glycophorin C and band 3. The interaction with band 4.1 and p55 is mediated by the N terminal 30 kD domain of band 4.1 binding to a 16 amino acid segment (residues 82-98: residues 61-77 of glycophorin D) within the cytoplasmic domain of glycophorin C and to a positively charged 39 amino acid motif in p55. The majority of protein 4.1 is bound to glycophorin C. The magnitude of the strength of the interaction between glycophorin C and band 4.1 has been estimated to be 6.9 microNewtons per meter, a figure typical of protein–protein interactions.
Glycophorin C normally shows oscillatory movement in the erythrocyte membrane. This is reduced in Southeast Asian ovalocytosis a disease of erythrocytes due to a mutation in band 3.
The Ge2 epitope is antigenic only on glycophorin D and is a cryptotope in glycophorin C. It is located within exon 2 and is sensitive to trypsin and papain but resistant to chymotrypsin and pronase. The Ge3 epitope is encoded by exon 3. It is sensitive to trypsin but resistant to chymotrypsin, papain and pronase. It is thought to lie in the between amino acids 42-50 in glycophorin C (residues 21-49 in glycophorin D). Ge4 is located within the first 21 amino acids of glycophorin C. It is sensitive to trypsin, papain, pronase and neuraminidase.
Glycophorin C mutations are rare in most of the Western world, but are more common in some places where malaria is endemic. In Melanesia a greater percentage of the population is Gerbich negative (46.5%) than in any other part of the world. The incidence of Gerbich-negative phenotype caused by an exon 3 deletion in the Wosera (East Sepik Province) and Liksul (Madang Province) populations of Papua New Guinea is 0.463 and 0.176 respectively.
Glycophorin C is the receptor for the protein erythrocyte binding antigen 140 (EBA140) of Plasmodium falciparum. This interaction mediates a principal invasion pathway into the erythrocytes. The partial resistance of erythrocytes lacking this protein to invasion by P. falciparum was first noted in 1982. The lack of Gerbich antigens in the population of Papua New Guinea was noted in 1989.
Influenza A and B bind to glycophorin C.
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