8.A.168.  The Glycophorin (GPh) Family 

Glycophorin A, GPhA or GPA, is the major intrinsic membrane protein of the erythrocyte (Blanchard 1990). The N-terminal glycosylated segment, which lies outside the erythrocyte membrane, has MN blood group receptor function (Altable and de la Serna 2021). This protein is important for the function of SLC4A1 (the anion exchanger (AE1, HCO3-:Cl- antiporter; also called Band 3, see TC# 2.A.31.1.1) and is required for high activity of SLC4A1. GPh may be involved in translocation of SLC4A1 to the plasma membrane (Cartron and Rahuel 1992. AE1 is the main erythroid Cl-/HCO3- transporter that supports CO2 transport. Glycophorin A (GPA), a component of AE1 complexes, facilitates AE1 expression and anion transport, but Glycophorin B (GPB) does not (Hsu et al. 2022).

GPA is a receptor for influenza virus and Hepatitis A virus, and it is a receptor for Plasmodium falciparum erythrocyte-binding antigen 175 (EBA-175) (see TC# 9.B.367.1.4); binding of EBA-175 is dependent on sialic acid residues of the O-linked glycans. Almost the entire populations of four transmembrane proteins, including glycophorin A, Band 2 (AI) and other erythrocyte membrane proteins, are immobilized by either the incorporation within large multiprotein complexes or entrapment within the protein network of the cortical spectrin cytoskeleton, preventing lateral diffusion (Kodippili et al. 2020). Folding and modulation of the helical conformation of Glycophorin A by point mutations have been studied, revealing the structural stability of GpA in a micellar environment, while taking secondary structural fluctuations into account (Lee et al. 2023).


 

References:

Altable, M. and J.M. de la Serna. (2021). Protection against COVID-19 in African population: Immunology, genetics, and malaria clues for therapeutic targets. Virus Res 299: 198347.

Blanchard, D. (1990). Human red cell glycophorins: biochemical and antigenic properties. Transfus Med Rev 4: 170-186.

Blazhynska, M., J.C. Gumbart, H. Chen, E. Tajkhorshid, B. Roux, and C. Chipot. (2023). A Rigorous Framework for Calculating Protein-Protein Binding Affinities in Membranes. J Chem Theory Comput 19: 9077-9092.

Cartron, J.P. and C. Rahuel. (1992). Human erythrocyte glycophorins: protein and gene structure analyses. Transfus Med Rev 6: 63-92.

Hsu, K., T.Y. Lee, J.Y. Lin, and P.L. Chen. (2022). A Balance between Transmembrane-Mediated ER/Golgi Retention and Forward Trafficking Signals in Glycophorin-Anion Exchanger-1 Interaction. Cells 11:.

Kodippili, G.C., K. Giger, K.S. Putt, and P.S. Low. (2020). DARC, Glycophorin A, Band 3, and GLUT1 Diffusion in Erythrocytes: Insights into Membrane Complexes. Biophys. J. 119: 1749-1759.

Lee, P.Y., A. Sahoo, and S. Matysiak. (2023). Folding and modulation of the helical conformation of Glycophorin A by point mutations. Phys Chem Chem Phys 25: 10885-10893.

Pasvol, G., B. Clough, and J. Carlsson. (1992). Malaria and the red cell membrane. Blood Rev 6: 183-192.

Takakuwa, Y. (2001). Regulation of red cell membrane protein interactions: implications for red cell function. Curr Opin Hematol 8: 80-84.

Examples:

TC#NameOrganismal TypeExample
8.A.168.1.1

Glycophorin A (GYPA or GPA) of 150 aas and 2 TMSs, one N-terminal and one near the C-terminus of the protein. Red blood cell sialoglycoproteins (glycophorins) play an important role in invasion by Plasmodium falciparum (Pasvol et al. 1992), but they also regulate the activities of several transport systems (see GP family description and Takakuwa 2001). GpA dimerization has been measured using molecular dynamics-based approaches that agree with experiments, and this allows the  protein-protein binding affinities in membranes (Blazhynska et al. 2023).

GPA of Homo sapiens

 
8.A.168.1.2

Glycophorin-A, GPA, isoform X1 of 230 aas and 2 TMSs, N- and C-terminal.

GPA of Sarcophilus harrisii

 
8.A.168.1.3

Glycophorin A, GPA, of 171 aas and 1 C-terminal TMS.  It may be N-terminally truncated. 

GPA of Meriones unguiculatus (Mongolian gerbil)

 
8.A.168.1.4

Glycophorin B, GPB, of 82 aas and 1 C-terminal TMS. (may be N-terminally truncated).

GPB of Homo sapiens