Definition of a physiologic aging autoantigen by using synthetic peptides of membrane protein band 3: localization of the active antigenic sites.

Kay, Marguerite M. B.; Marchalonis, John J.; Hughes, Julie; Watanabe, Kiyotaka; Schluter, Samuel F.

doi:10.1073/pnas.87.15.5734

Proc. Natl. Acad. Sci. U.S.A.

1990

DOI: 10.1073/pnas.87.15.5734

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Definition of a physiologic aging autoantigen by using synthetic peptides of membrane protein band 3: localization of the active antigenic sites.

Marguerite M. B. Kay

John J. Marchalonis

Julie Hughes

et al.

Abstract: Senescent cell antigen (SCA), an aging antigen, is a protein that appears on old cells and marks them for removal by the immune system in mammals. It is derived from band 3, a ubiquitous membrane transport protein found in diverse cell types and tissues. We have used synthetic peptides to identify aging antigenic sites on band 3, using a competitive inhibition assay and immunoblotting with IgG directed against the aging antigen on old cells. Results indicate that: (i) the active antigenic sites of the aging an… Show more

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Cited by 57 publications

(54 citation statements)

References 36 publications

(48 reference statements)

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“…Also, the Asp 821 -His 834 region is involved in the adhesion of malaria-infected erythrocytes to endothelial cells (5). This stretch was also identified as the senescence antigen of aged erythrocytes (17). Some proteolytic sites in the AE1 C-terminal region were accessible only after treatment of erythrocytes with high concentrations of sodium hydroxide, suggesting that those regions normally are folded into the AE1 structure (18).…”

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confidence: 99%

Novel Topology in C-terminal Region of the Human Plasma Membrane Anion Exchanger, AE1

Zhu

Lee

Casey

2003

Journal of Biological Chemistry

139

178

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Human AE1 performs electroneutral exchange of Cl ؊ for HCO 3 ؊ across the erythrocyte membrane. We examined the topology of the AE1 C-terminal region using cysteine-scanning mutagenesis and sulfhydryl-specific chemistry. Eighty individual cysteine residues, introduced into an otherwise cysteine-less mutant between were inaccessible to the extracellular medium and thus localized to the intracellular surface of AE1. Functional assays revealed that one face of each of two AE1 TMs was sensitive to mutation. Based on these results, we propose a topology model for the C-terminal region of the membrane domain of human AE1.

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mentioning

confidence: 99%

Novel Topology in C-terminal Region of the Human Plasma Membrane Anion Exchanger, AE1

Zhu

Lee

Casey

2003

Journal of Biological Chemistry

139

178

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“…2 (8,9) of band 3 coupled with information about which residues are reactive in intact cells (9)(10)(11)(12)(13) was used to predict the regions of the band 3 molecule that are exofacial. Division of sequences into external loop regions was based on hydropathy plots (9) and published information (14,15). The initial choice of peptide sequence was based on the observation that a histidine, a lysine, and two tyrosine residues [residues thought to be involved in cytoadherence (16,17)] were present in the region encompassing amino acids 547-555.…”

mentioning

confidence: 99%

Synthetic peptides based on motifs present in human band 3 protein inhibit cytoadherence/sequestration of the malaria parasite Plasmodium falciparum.

Crandall

Collins

Gysin

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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Synthetic peptides patterned on the amino acid sequences found in two exofacial regions of band 3 protein (residues 824-829 of loop 7 and residues 547-553 of loop 3) blocked, in a dose-dependent fashion, the in vitro adherence of Plasmodium falciparum-infected erythrocytes to C32 amelanotic melanoma cells. Intravenous infusion of these synthetic peptides into Aotus and Saimiri monkeys infected with sequestering isolates of P. fakciparum resulted in the appearance of mature forms of the parasite in the peripheral circulation. The finding that the peptides were effective as adhesion blockers in the micromolar range suggests that cerebral malaria could be managed through antiadhesion therapy.The hallmark ofPlasmodiumfalciparum infections is sequestration-that is, the attachment of erythrocytes infected with mature-stage parasites (trophozoites/schizonts) to the endothelial cells lining the postcapillary venules (1). In humans, the principal organs in which sequestration takes place are the heart, lung, kidney, and liver (2). Sequestration in the brain microvessels-a special pathology of P. falciparum infections called cerebral malaria-may occlude blood flow and result in confusion, lethargy, and deep coma (3). Although the plasmodial molecules on the surface of the malaria-infected erythrocyte that are responsible for binding to the endothelium have not been identified, a parasite-encoded protein, P. falciparum erythrocyte membrane protein 1 (PfEMP 1; ref. 4), similar to a recently described protein called sequestrin (5), has been correlated with cytoadherence. However, the precise role of PfEMP 1 (or sequestrin) in erythrocyte sequestration has not been determined.Earlier work (5-7) indicated that infection of erythrocytes by the malaria parasite P. falciparum leads to truncated forms ofband 3 protein in the erythrocyte membrane and that these were involved in the cytoadherent behavior of the infected erythrocyte. Further, several monoclonal antibodies directed against exofacial loops 3 and 7 of band 3 protein blocked cytoadherence (I.C. and I.W.S., unpublished results). In an attempt to further define the regions of band 3 protein responsible for the cytoadherent behavior of infected erythrocytes, peptides patterned on the surface-exposed domains of band 3 were synthesized, and their ability to inhibit the in vitro and in vivo adherence of P. falciparuminfected erythrocyte was determined.The following observations were used to determine which sequences in the exofacial loops (Fig. 1) might contain the adhesive region: (i) Cytoadherence is strongly influenced by pH (16,17), consistent with a protonated histidine residue being near to, or part of, the adhesin site. (ii) Cytoadherence is strongly inhibited by the iodination of surface proteins of a P. falciparum-infected erythrocyte (18), implying that a tyrosine residue is near to, or part of, the adhesin site. (iii) The adhesin is trypsin sensitive (18), suggesting that a trypsin site (a lysine or arginine) is close to, or part of, the adhesive region. Bec...

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“…Senescent cell antigen is generated on the transport domain. Senescent cell antigen is a protein that appears on old cells and acts as a specific signal for the termination of that cell by initiating the binding of IgG autoantibody and subsequent removal by phagocytes (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)). This appears to be a general physiologic process for removing senescent and damaged cells in mammals and other vertebrates (21).…”

mentioning

confidence: 99%

“…Degradation of band 3 generates senescent cell antigen, an antigen of aging cells (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Senescent cell antigen is generated on the transport domain.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Brain membrane protein band 3 performs the same functions as erythrocyte band 3.

Kay¹,

Hughes²,

Zagon³

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

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We report the presence of band 3 protein(s) in mammalian brain that performs the same functions as those of erythroid band 3. These functions are anion transport, ankyrin binding, and generation of senescent cell antigen, an aging antigen that terminates the life of cells. Structural similarity of brain and erythroid band 3 is suggested by the reaction of antibodies to synthetic peptides of erythroid band 3 with brain band 3, the inhibition ofanion transport by the same inhibitors, and an equal degree of inhibition of brain and erythrocyte anion transport by synthetic peptides of erythroid band 3 (pep-ANION 2, residues 588-602; pep-COOH, residues 812-827; pep-COOH-N6, residues 813-818). One ofthese segments, pep-COOH, contains antigenic determinants of senescent cell antigen. These findings suggest that the transport domains of erythroid and neural band 3 are similar functionally and structurally and support the hypothesis that the immunological mechanism of maintaining homeostasis is a general physiologic process for removing senescent and damaged cells in mammals and other vertebrates.

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Definition of a physiologic aging autoantigen by using synthetic peptides of membrane protein band 3: localization of the active antigenic sites.

Cited by 57 publications

References 36 publications

Novel Topology in C-terminal Region of the Human Plasma Membrane Anion Exchanger, AE1

Novel Topology in C-terminal Region of the Human Plasma Membrane Anion Exchanger, AE1

Synthetic peptides based on motifs present in human band 3 protein inhibit cytoadherence/sequestration of the malaria parasite Plasmodium falciparum.

Brain membrane protein band 3 performs the same functions as erythrocyte band 3.

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