Probing the conformational and dynamical effects of O‐glycosylation within the immunodominant region of a MUC1 peptide tumor antigen
Identifieur interne : 003255 ( Main/Exploration ); précédent : 003254; suivant : 003256Probing the conformational and dynamical effects of O‐glycosylation within the immunodominant region of a MUC1 peptide tumor antigen
Auteurs : J. Schuman [États-Unis] ; A. P. Campbell [États-Unis] ; R. R. Koganty [Canada] ; B. M. Longenecker [Canada]Source :
- The Journal of Peptide Research [ 1397-002X ] ; 2003-03.
Abstract
Abstract: MUC1 mucin is a large transmembrane glycoprotein, the extracellular domain of which is formed by a repeating 20 amino acid sequence, GVTSAPDTRPAPGSTAPPAH. In normal breast epithelial cells, the extracellular domain is densely covered with highly branched complex carbohydrate structures. However, in neoplastic breast tissue, the extracellular domain is under‐glycosylated, resulting in the exposure of a highly immunogenic core peptide epitope (PDTRP in bold above), as well as in the exposure of normally cryptic core Tn (GalNAc), STn (sialyl α2–6 GalNAc) and TF (Gal β1–3 GalNAc) carbohydrates. Here, we report the results of 1H NMR structural studies, natural abundance 13C NMR relaxation measurements and distance‐restrained MD simulations designed to probe the structural and dynamical effects of Tn‐glycosylation within the PDTRP core peptide epitope. Two synthetic peptides were studied: a nine‐residue MUC1 peptide of the sequence, Thr1‐Ser2‐Ala3‐Pro4‐Asp5‐Thr6‐Arg7‐Pro8‐Ala9, and a Tn‐glycosylated version of this peptide, Thr1‐Ser2‐Ala3‐Pro4‐Asp5‐Thr6(αGalNAc)‐Arg7‐Pro8‐Ala9. The results of these studies show that a type I β‐turn conformation is adopted by residues PDTR within the PDTRP region of the unglycosylated MUC1 sequence. The existence of a similar β‐turn within the PDTRP core peptide epitope of the under‐glycosylated cancer‐associated MUC1 mucin protein might explain the immunodominance of this region in vivo, as the presence of defined secondary structure within peptide epitope regions has been correlated with increased immunogenicity in other systems. Our results have also shown that Tn glycosylation at the central threonine within the PDTRP core epitope region shifts the conformational equilibrium away from the type I β‐turn conformation and toward a more rigid and extended state. The significance of these results are discussed in relation to the possible roles that peptide epitope secondary structure and glycosylation state may play in MUC1 tumor immunogenicity.
Url:
DOI: 10.1034/j.1399-3011.2003.00031.x
Affiliations:
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Schuman</name><affiliation wicri:level="4"><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle</wicri:regionArea><orgName type="university">Université de Washington</orgName><placeName><settlement type="city">Seattle</settlement><region type="state">Washington (État)</region></placeName></affiliation></author><author><name sortKey="Campbell, A P" sort="Campbell, A P" uniqKey="Campbell A" first="A. P." last="Campbell">A. P. Campbell</name><affiliation wicri:level="4"><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle</wicri:regionArea><orgName type="university">Université de Washington</orgName><placeName><settlement type="city">Seattle</settlement><region type="state">Washington (État)</region></placeName></affiliation></author><author><name sortKey="Koganty, R R" sort="Koganty, R R" uniqKey="Koganty R" first="R. R." last="Koganty">R. R. Koganty</name><affiliation wicri:level="1"><country xml:lang="fr">Canada</country><wicri:regionArea>Biomira Inc., Edmonton</wicri:regionArea><wicri:noRegion>Edmonton</wicri:noRegion></affiliation></author><author><name sortKey="Longenecker, B M" sort="Longenecker, B M" uniqKey="Longenecker B" first="B. M." last="Longenecker">B. M. 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In normal breast epithelial cells, the extracellular domain is densely covered with highly branched complex carbohydrate structures. However, in neoplastic breast tissue, the extracellular domain is under‐glycosylated, resulting in the exposure of a highly immunogenic core peptide epitope (PDTRP in bold above), as well as in the exposure of normally cryptic core Tn (GalNAc), STn (sialyl α2–6 GalNAc) and TF (Gal β1–3 GalNAc) carbohydrates. Here, we report the results of 1H NMR structural studies, natural abundance 13C NMR relaxation measurements and distance‐restrained MD simulations designed to probe the structural and dynamical effects of Tn‐glycosylation within the PDTRP core peptide epitope. Two synthetic peptides were studied: a nine‐residue MUC1 peptide of the sequence, Thr1‐Ser2‐Ala3‐Pro4‐Asp5‐Thr6‐Arg7‐Pro8‐Ala9, and a Tn‐glycosylated version of this peptide, Thr1‐Ser2‐Ala3‐Pro4‐Asp5‐Thr6(αGalNAc)‐Arg7‐Pro8‐Ala9. The results of these studies show that a type I β‐turn conformation is adopted by residues PDTR within the PDTRP region of the unglycosylated MUC1 sequence. The existence of a similar β‐turn within the PDTRP core peptide epitope of the under‐glycosylated cancer‐associated MUC1 mucin protein might explain the immunodominance of this region in vivo, as the presence of defined secondary structure within peptide epitope regions has been correlated with increased immunogenicity in other systems. Our results have also shown that Tn glycosylation at the central threonine within the PDTRP core epitope region shifts the conformational equilibrium away from the type I β‐turn conformation and toward a more rigid and extended state. The significance of these results are discussed in relation to the possible roles that peptide epitope secondary structure and glycosylation state may play in MUC1 tumor immunogenicity.</div></front></TEI><affiliations><list><country><li>Canada</li><li>États-Unis</li></country><region><li>Washington (État)</li></region><settlement><li>Seattle</li></settlement><orgName><li>Université de Washington</li></orgName></list><tree><country name="États-Unis"><region name="Washington (État)"><name sortKey="Schuman, J" sort="Schuman, J" uniqKey="Schuman J" first="J." last="Schuman">J. Schuman</name></region><name sortKey="Campbell, A P" sort="Campbell, A P" uniqKey="Campbell A" first="A. P." last="Campbell">A. P. Campbell</name></country><country name="Canada"><noRegion><name sortKey="Koganty, R R" sort="Koganty, R R" uniqKey="Koganty R" first="R. R." last="Koganty">R. R. Koganty</name></noRegion><name sortKey="Longenecker, B M" sort="Longenecker, B M" uniqKey="Longenecker B" first="B. M." last="Longenecker">B. M. Longenecker</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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