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).
History The antigen was discovered in 1960 when three women who lacked the antigen made anti-Gea in response to pregnancy. The antigen is named after one of the patients – a Mrs Gerbich. The following year a new but related antigen was discovered in a Mrs Yus for whom an antigen in this system is also named. In 1972 a numerical system for the antigens in this blood group was introduced.
Genomics Despite the similar names glycophorin C and D are unrelated to the other three glycophorins which encoded on chromosome 4 at location 4q28-q31. These latter proteins are closely related. Glycophorin A and glycophorin B carry the blood group MN and Ss antigens respectively. There are ~225,000 molecules of GPC and GPD per erythrocyte. 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 translation 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 exons 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 isoforms 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 glycosylated. 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 Kell antigens, Rhesus-associated glycoprotein, 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.
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