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Immunogenetics Jun 2023Glycophorins are transmembrane proteins of red blood cells (RBCs), heavily glycosylated on their external-facing surface. In humans, there are four glycophorin proteins,... (Review)
Review
Glycophorins are transmembrane proteins of red blood cells (RBCs), heavily glycosylated on their external-facing surface. In humans, there are four glycophorin proteins, glycophorins A, B, C and D. Glycophorins A and B are encoded by two similar genes GYPA and GYPB, and glycophorin C and glycophorin D are encoded by a single gene, GYPC. The exact function of glycophorins remains unclear. However, given their abundance on the surface of RBCs, it is likely that they serve as a substrate for glycosylation, giving the RBC a negatively charged, complex glycan "coat". GYPB and GYPE (a closely related pseudogene) were generated from GYPA by two duplication events involving a 120-kb genomic segment between 10 and 15 million years ago. Non-allelic homologous recombination between these 120-kb repeats generates a variety of duplication alleles and deletion alleles, which have been systematically catalogued from genomic sequence data. One allele, called DUP4, encodes the Dantu NE blood type and is strongly protective against malaria as it alters the surface tension of the RBC membrane. Glycophorins interact with other infectious pathogens, including viruses, as well as the malarial parasite Plasmodium falciparum, but the role of glycophorin variation in mediating the effects of these pathogens remains underexplored.
Topics: Humans; Glycophorins; Erythrocytes; Membrane Proteins; Communicable Diseases; Genetic Variation
PubMed: 36224278
DOI: 10.1007/s00251-022-01280-7 -
Transfusion Medicine Reviews Apr 2018Antigens of the Gerbich blood group system are expressed on glycophorin C (GPC) and glycophorin D (GPD), minor sialoglycoproteins of human erythrocytes. GPC and GPD help... (Review)
Review
Antigens of the Gerbich blood group system are expressed on glycophorin C (GPC) and glycophorin D (GPD), minor sialoglycoproteins of human erythrocytes. GPC and GPD help maintain erythrocyte shape of and contributes to the stability of its membrane. There are six high-prevalence Gerbich antigens: Ge2, Ge3, Ge4, GEPL (GE10), GEAT (GE11), GETI (GE12) and five low-prevalence Gerbich antigens: Wb (GE5), Ls (GE6), An (GE7), Dh (GE8), GEIS (GE9). Some Gerbich antigens (Ge4, Wb, Dh, GEAT) are expressed only on GPC, two (Ge2, An) are expressed only on GPD, while others (Ge3, Ls, GEIS, GEPL, GETI) are expressed on both GPC and GPD. Antibodies recognizing GPC/GPD may arise naturally (so-called "naturally-occurring RBC antibodies") or as the result of alloimmunization, and some of them may be clinically relevant. Gerbich antibodies usually do not cause serious hemolytic transfusion reactions (HTR); autoantibodies of anti-Ge2- or anti-Ge3 specificity can cause autoimmune hemolytic anemia (AIHA).
Topics: Anemia, Hemolytic, Autoimmune; Antibodies, Monoclonal; Blood Group Antigens; Erythrocyte Membrane; Erythrocytes; Glycophorins; Hemolysis; Humans; Ligands; Malaria; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Prevalence; Protein Domains
PubMed: 29540278
DOI: 10.1016/j.tmrv.2018.02.004 -
Biophysical Journal Jun 2022In the erythrocyte membrane, the interactions between glycophorin A (GPA) and Band 3 are associated strongly with the biological function of the membrane and several...
In the erythrocyte membrane, the interactions between glycophorin A (GPA) and Band 3 are associated strongly with the biological function of the membrane and several blood disorders. In this work, using coarse-grained molecular-dynamics simulations, we systematically investigate the effects of cholesterol and phosphatidylinositol-4,5-bisphosphate (PIP2) on the interactions of GPA with Band 3 in the model erythrocyte membranes. We examine the dynamics of the interactions of GPA with Band 3 in different lipid bilayers on the microsecond time scale and calculate the binding free energy between GPA and Band 3. The results indicate that cholesterols thermodynamically favor the binding of GPA to Band 3 by increasing the thickness of the lipid bilayer and by producing an effective attraction between the proteins due to the depletion effect. Cholesterols also slow the kinetics of the binding of GPA to Band 3 by reducing the lateral mobility of the lipids and proteins and may influence the binding sites between the proteins. The anionic PIP2 lipids prefer binding to the surface of the proteins through electrostatic attraction between the PIP2 headgroup and the positively charged residues on the protein surface. Ions in the solvent facilitate PIP2 aggregation, which promotes the binding of GPA to Band 3.
Topics: Cholesterol; Erythrocyte Membrane; Glycophorins; Lipid Bilayers; Molecular Dynamics Simulation
PubMed: 35524411
DOI: 10.1016/j.bpj.2022.05.001 -
Biomolecules Nov 2022The key element in developing a successful malaria treatment is a good understanding of molecular mechanisms engaged in human host infection. It is assumed that... (Review)
Review
The key element in developing a successful malaria treatment is a good understanding of molecular mechanisms engaged in human host infection. It is assumed that oligosaccharides play a significant role in parasites binding to RBCs at different steps of host infection. The formation of a tight junction between EBL merozoite ligands and glycophorin receptors is the crucial interaction in ensuring merozoite entry into RBCs. It was proposed that sialic acid residues of O/N-linked glycans form clusters on a human glycophorins polypeptide chain, which facilitates the binding. Therefore, specific carbohydrate drugs have been suggested as possible malaria treatments. It was shown that the sugar moieties of -acetylneuraminyl--acetate-lactosamine and 2,3-didehydro-2-deoxy--acetylneuraminic acid (DANA), which is its structural analog, can inhibit EBA-175-GPA interaction. Moreover, heparin-like molecules might be used as antimalarial drugs with some modifications to overcome their anticoagulant properties. Assuming that the principal interactions of merozoites and host cells are mediated by carbohydrates or glycan moieties, glycobiology-based approaches may lead to new malaria therapeutic targets.
Topics: Humans; Plasmodium falciparum; Glycophorins; Erythrocytes; Plasmodium; Malaria, Falciparum; Malaria; Oligosaccharides; Polysaccharides
PubMed: 36421683
DOI: 10.3390/biom12111669 -
Parasites & Vectors Jun 2019Glycophorins are heavily glycosylated sialoglycoproteins of human and animal erythrocytes. In humans, there are four glycophorins: A, B, C and D. Glycophorins play an... (Review)
Review
Glycophorins are heavily glycosylated sialoglycoproteins of human and animal erythrocytes. In humans, there are four glycophorins: A, B, C and D. Glycophorins play an important role in the invasion of red blood cells (RBCs) by malaria parasites, which involves several ligands binding to RBC receptors. Four Plasmodium falciparum merozoite EBL ligands have been identified: erythrocyte-binding antigen-175 (EBA-175), erythrocyte-binding antigen-181 (EBA-181), erythrocyte-binding ligand-1 (EBL-1) and erythrocyte-binding antigen-140 (EBA-140). It is generally accepted that glycophorin A (GPA) is the receptor for P. falciparum EBA-175 ligand. It has been shown that α(2,3) sialic acid residues of GPA O-glycans form conformation-dependent clusters on GPA polypeptide chain which facilitate binding. P. falciparum can also invade erythrocytes using glycophorin B (GPB), which is structurally similar to GPA. It has been shown that P. falciparum EBL-1 ligand binds to GPB. Interestingly, a hybrid GPB-GPA molecule called Dantu is associated with a reduced risk of severe malaria and ameliorates malaria-related morbidity. Glycophorin C (GPC) is a receptor for P. falciparum EBA-140 ligand. Likewise, successful binding of EBA-140 depends on sialic acid residues of N- and O-linked oligosaccharides of GPC, which form a cluster or a conformational structure depending on the presence of peptide fragment encompassing amino acids (aa) 36-63. Evaluation of the homologous P. reichenowi EBA-140 unexpectedly revealed that the chimpanzee homolog of human glycophorin D (GPD) is probably the receptor for this ligand. In this review, we concentrate on the role of glycophorins as erythrocyte receptors for Plasmodium parasites. The presented data support the long-lasting idea of high evolutionary pressure exerted by Plasmodium on the human glycophorins, which emerge as important receptors for these parasites.
Topics: Animals; Carrier Proteins; Erythrocytes; Glycophorins; Humans; Ligands; Membrane Proteins; Merozoites; Pan troglodytes; Plasmodium falciparum; Protein Binding; Protozoan Proteins; Receptors, Cell Surface
PubMed: 31234897
DOI: 10.1186/s13071-019-3575-8 -
Cells Nov 2022Anion exchanger-1 (AE1) is the main erythroid Cl/HCO transporter that supports CO transport. Glycophorin A (GPA), a component of the AE1 complexes, facilitates AE1...
Anion exchanger-1 (AE1) is the main erythroid Cl/HCO transporter that supports CO transport. Glycophorin A (GPA), a component of the AE1 complexes, facilitates AE1 expression and anion transport, but Glycophorin B (GPB) does not. Here, we dissected the structural components of GPA/GPB involved in glycophorin-AE1 trafficking by comparing them with three GPB variants-GPBhead (lacking the transmembrane domain [TMD]), GPBtail (mainly the TMD), and GP.Mur (glycophorin B-A-B hybrid). GPB-derived GP.Mur bears an O-glycopeptide that encompasses the R18 epitope, which is present in GPA but not GPB. By flow cytometry, AE1 expression in the control erythrocytes increased with the GPA-R18 expression; erythrocytes bearing both GP.Mur and GPA expressed more R18 epitopes and more AE1 proteins. In contrast, heterologously expressed GPBtail and GPB were predominantly localized in the Golgi apparatus of HEK-293 cells, whereas GBhead was diffuse throughout the cytosol, suggesting that glycophorin transmembrane encoded an ER/Golgi retention signal. AE1 coexpression could reduce the ER/Golgi retention of GPB, but not of GPBtail or GPBhead. Thus, there are forward-trafficking and transmembrane-driven ER/Golgi retention signals encoded in the glycophorin sequences. How the balance between these opposite trafficking signals could affect glycophorin sorting into AE1 complexes and influence erythroid anion transport remains to be explored.
Topics: Humans; Glycophorins; HEK293 Cells; Erythrocytes; Golgi Apparatus; Anions
PubMed: 36359907
DOI: 10.3390/cells11213512 -
Mutation Research. Reviews in Mutation... 2020An underappreciated aspect of human mutagenicity biomonitoring is tissue specificity reflected in different assays, especially those that measure events that can only... (Review)
Review
An underappreciated aspect of human mutagenicity biomonitoring is tissue specificity reflected in different assays, especially those that measure events that can only occur in developing bone marrow (BM) cells. Reviewed here are 9 currently-employed human mutagenicity biomonitoring assays. Several assays measure chromosome-level events in circulating T-lymphocytes (T-cells), i.e., traditional analyses of aberrations, translocation studies involving chromosome painting and fluorescence in situ hybridization (FISH) and determinations of micronuclei (MN). Other T-cell assays measure gene mutations. i.e., hypoxanthine-guanine phosphoriboslytransferase (HPRT) and phosphoribosylinositol glycan class A (PIGA). In addition to the T-cell assays, also reviewed are those assays that measure events in peripheral blood cells that necessarily arose in BM cells, i.e., MN in reticulocytes; glycophorin A (GPA) gene mutations in red blood cells (RBCs), and PIGA gene mutations in RBC or granulocytes. This review considers only cell culture- or cytometry-based assays to describe endpoints measured, methods, optimal sampling times, and sample summaries of typical quantitative and qualitative results. However, to achieve its intended focus on the target cells where events occur, kinetics of the cells of peripheral blood that derive at some point from precursor cells are reviewed to identify body sites and tissues where the genotoxic events originate. Kinetics indicate that in normal adults, measured events in T-cells afford global assessments of in vivo mutagenicity but are not specific for BM effects. Therefore, an agent's capacity for inducing mutations in BM cells cannot be reliably inferred from T-cell assays as the magnitude of effect in BM, if any, is unknown. By contrast, chromosome or gene level mutations measured in RBCs/reticulocytes or granulocytes must originate in BM cells, i.e. in RBC or granulocyte precursors, thereby making them specific indicators for effects in BM. Assays of mutations arising directly in BM cells may quantitatively reflect the mutagenicity of potential leukemogenic agents.
Topics: Adult; Bone Marrow; Chromosome Aberrations; Erythrocytes; Glycophorins; Humans; In Situ Hybridization, Fluorescence; Mutagenicity Tests; Mutation; Reticulocytes
PubMed: 33339577
DOI: 10.1016/j.mrrev.2020.108341 -
BMC Genomics Jun 2020Approximately 5% of the human genome shows common structural variation, which is enriched for genes involved in the immune response and cell-cell interactions. A...
BACKGROUND
Approximately 5% of the human genome shows common structural variation, which is enriched for genes involved in the immune response and cell-cell interactions. A well-established region of extensive structural variation is the glycophorin gene cluster, comprising three tandemly-repeated regions about 120 kb in length and carrying the highly homologous genes GYPA, GYPB and GYPE. Glycophorin A (encoded by GYPA) and glycophorin B (encoded by GYPB) are glycoproteins present at high levels on the surface of erythrocytes, and they have been suggested to act as decoy receptors for viral pathogens. They are receptors for the invasion of the protist parasite Plasmodium falciparum, a causative agent of malaria. A particular complex structural variant, called DUP4, creates a GYPB-GYPA fusion gene known to confer resistance to malaria. Many other structural variants exist across the glycophorin gene cluster, and they remain poorly characterised.
RESULTS
Here, we analyse sequences from 3234 diploid genomes from across the world for structural variation at the glycophorin locus, confirming 15 variants in the 1000 Genomes project cohort, discovering 9 new variants, and characterising a selection of these variants using fibre-FISH and breakpoint mapping at the sequence level. We identify variants predicted to create novel fusion genes and a common inversion duplication variant at appreciable frequencies in West Africans. We show that almost all variants can be explained by non-allelic homologous recombination and by comparing the structural variant breakpoints with recombination hotspot maps, confirm the importance of a particular meiotic recombination hotspot on structural variant formation in this region.
CONCLUSIONS
We identify and validate large structural variants in the human glycophorin A-B-E gene cluster which may be associated with different clinical aspects of malaria.
Topics: Chromosome Breakpoints; Chromosome Mapping; Databases, Genetic; Disease Resistance; Genomic Structural Variation; Glycophorins; Humans; In Situ Hybridization, Fluorescence; Malaria, Falciparum; Sequence Alignment; Whole Genome Sequencing
PubMed: 32600246
DOI: 10.1186/s12864-020-06849-8 -
The Yale Journal of Biology and Medicine 1990Recognition and application of blood group differences on human red cells permitted the development of safe procedures for blood transfusion. Blood group antigens are... (Review)
Review
Recognition and application of blood group differences on human red cells permitted the development of safe procedures for blood transfusion. Blood group antigens are markers on surface-exposed red cell proteins or the sugar moiety of glycoproteins or glycolipids. Apart from their presumed biological function, some antigens have been identified as receptors for host/parasite interactions. Thus, carbohydrates that determine P antigenicity are the binding receptor for certain strains of pyelonephritic coliforms. Other pathogenic coliforms bind to the membrane structure that carries the Dra antigen. A structure associated with Duffy antigens is the attachment receptor for the parasite of Plasmodium vivax malaria, while Plasmodium falciparum parasites bind to structures associated with membrane glycophorins. Structure/function relationships have been established by the finding that lack of Rh protein in red cells of Rhnull phenotype is associated with stomatocytic cell morphology and a hemolytic state. Absence of glycophorin C, and the Gerbich blood group antigens that it carries, is associated with elliptocytic red cells. Absence of Kx antigen protein in the Kell system is associated with the McLeod blood group phenotype, with acanthocytic cell morphology and reduced in vivo survival. McLeod individuals also have late-onset muscular dystrophy and neurological disorders.
Topics: Bacterial Outer Membrane Proteins; Blood Group Antigens; Carrier Proteins; Glycophorins; HLA-DR Antigens; Host-Parasite Interactions; Humans; Kell Blood-Group System; Receptors, Cell Surface
PubMed: 2293504
DOI: No ID Found -
Scientific Reports Apr 2023Mass spectrometry (MS)-based proteomics has recently attracted the attention from forensic pathologists. This work is the first report of the development of a shotgun...
Mass spectrometry (MS)-based proteomics has recently attracted the attention from forensic pathologists. This work is the first report of the development of a shotgun bottom-up proteomic approach based on rapid protein extraction and nano-liquid chromatography/high-resolution mass spectrometry applied to full-thickness human skin for the differential analysis of normal and ecchymotic tissues to identify new biomarkers for bruise characterization and dating. We identified around 2000 proteins from each pooled extract. The method showed excellent precision on independent replicates, with Pearson correlation coefficients always higher than 95%. Glycophorin A, a known biomarker of vital wounds from immunochemical studies, was identified only in ecchymotic tissues, as confirmed by Western blotting analysis. This finding suggests that this protein can be used as a MS-detectable biomarker of wound vitality. By focusing on skin samples from individuals with known wound dating, besides Glycophorin A, other proteins differentially expressed in ecchymotic samples and dependant on wound age were identified, although further analysis on larger datasets are needed to validate these findings. This study paves the way for an in-depth investigation of the potential of MS-based techniques for wound examination in forensic pathology, overcoming the limitations of immunochemical assays.
Topics: Humans; Glycophorins; Tandem Mass Spectrometry; Proteomics; Forensic Pathology; Proteins; Biomarkers
PubMed: 37059833
DOI: 10.1038/s41598-023-32520-9