New insights into molecular recognition of epitopes related to MUC1 human mucin by lectins
Tn antigen ( -O-GalNAc-Ser/Thr) is one of the most specific human tumorassociated structures. This motif is implicated in HIV infection and it is expressed early in tumor cells. It has been observed that there is a direct correlation between carcinoma aggressiveness and the density of this antigen....
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Universidad de La Rioja (España)
2015
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Tn antigen ( -O-GalNAc-Ser/Thr) is one of the most specific human tumorassociated
structures. This motif is implicated in HIV infection and it is
expressed early in tumor cells. It has been observed that there is a direct
correlation between carcinoma aggressiveness and the density of this
antigen. For this reason, Tn determinant is a convenient cancer biomarker.
Mucin-like glycopeptides and glycoproteins, in particular MUC1, incorporate
this structure in their sequence. While in normal cells this O-glycosylated
protein carries complex oligosaccharides, in cancer cells, MUC1 expression is
increased and its glycans are short and poorly branched. Therefore, Tn
antigen is now exposed to the immune system generating an immunological
response.
From a structural point of view, Tn antigen is referred to Nacetylgalactosamine
(GalNAc) -O-linked to serine (Ser) or threonine (Thr),
not discriminating the amino acid to which GalNAc is linked. However, in this
Thesis, we have synthesized different representative MUC1 epitopes bearing
Ser and Thr in their structure and we have detected differences between
these two amino acids in terms of affinity to lectins. As a result, it is
important to mention specifically the underlying amino acid in Tn antigen.
We have also analyzed the role of flanking amino acids of Tn antigen in the
peptide chain, getting surprising results in terms of affinity to lectins. In
addition, we have obtained an X-ray structure by the first time of soybean
agglutinin (SBA) lectin linked to a MUC1-derived glycopeptide.
All these results may have important implications for better understanding
the glycopeptide-lectin interactions and may contribute to engineer new
binding sites, allowing the design of novel glycosensors for Tn antigen
detection in tumor cells. |
| author2 |
Peregrina García, Jesús Manuel (Universidad de La Rioja) |
| author_facet |
Peregrina García, Jesús Manuel (Universidad de La Rioja) Madariaga Merino, David |
| format |
text (thesis) |
| author |
Madariaga Merino, David |
| spellingShingle |
Madariaga Merino, David New insights into molecular recognition of epitopes related to MUC1 human mucin by lectins |
| author_sort |
Madariaga Merino, David |
| title |
New insights into molecular recognition of epitopes related to MUC1 human mucin by lectins |
| title_short |
New insights into molecular recognition of epitopes related to MUC1 human mucin by lectins |
| title_full |
New insights into molecular recognition of epitopes related to MUC1 human mucin by lectins |
| title_fullStr |
New insights into molecular recognition of epitopes related to MUC1 human mucin by lectins |
| title_full_unstemmed |
New insights into molecular recognition of epitopes related to MUC1 human mucin by lectins |
| title_sort |
new insights into molecular recognition of epitopes related to muc1 human mucin by lectins |
| publisher |
Universidad de La Rioja (España) |
| publishDate |
2015 |
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https://dialnet.unirioja.es/servlet/oaites?codigo=44390 |
| work_keys_str_mv |
AT madariagamerinodavid newinsightsintomolecularrecognitionofepitopesrelatedtomuc1humanmucinbylectins |
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1718346624014483456 |
| spelling |
oai-TES00000075352019-07-06New insights into molecular recognition of epitopes related to MUC1 human mucin by lectinsMadariaga Merino, DavidTn antigen ( -O-GalNAc-Ser/Thr) is one of the most specific human tumorassociated structures. This motif is implicated in HIV infection and it is expressed early in tumor cells. It has been observed that there is a direct correlation between carcinoma aggressiveness and the density of this antigen. For this reason, Tn determinant is a convenient cancer biomarker. Mucin-like glycopeptides and glycoproteins, in particular MUC1, incorporate this structure in their sequence. While in normal cells this O-glycosylated protein carries complex oligosaccharides, in cancer cells, MUC1 expression is increased and its glycans are short and poorly branched. Therefore, Tn antigen is now exposed to the immune system generating an immunological response. From a structural point of view, Tn antigen is referred to Nacetylgalactosamine (GalNAc) -O-linked to serine (Ser) or threonine (Thr), not discriminating the amino acid to which GalNAc is linked. However, in this Thesis, we have synthesized different representative MUC1 epitopes bearing Ser and Thr in their structure and we have detected differences between these two amino acids in terms of affinity to lectins. As a result, it is important to mention specifically the underlying amino acid in Tn antigen. We have also analyzed the role of flanking amino acids of Tn antigen in the peptide chain, getting surprising results in terms of affinity to lectins. In addition, we have obtained an X-ray structure by the first time of soybean agglutinin (SBA) lectin linked to a MUC1-derived glycopeptide. All these results may have important implications for better understanding the glycopeptide-lectin interactions and may contribute to engineer new binding sites, allowing the design of novel glycosensors for Tn antigen detection in tumor cells.El antígeno Tn ( -O-GalNAc-Ser/Thr) es una de las estructuras asociadas a tumores más específicas en humanos. Esta molécula está implicada en la infección del VIH y en su expresión temprana en células tumorales. También se ha observado una relación directa entre la agresividad de un carcinoma y la concentración de dicho antígeno. Por ello, el antígeno Tn está considerado como un importante biomarcador del cáncer. Los glicopéptidos y glicoproteínas tipo mucina, en particular la mucina humana MUC1, incorporan en su estructura el antígeno Tn. Mientras que en las células sanas esta O-glicoproteína de membrana tiene oligosacáridos complejos, en células cancerosas, la expresión de MUC1 aumenta y sus glicanos son cortos y poco ramificados. Esto hace que el antígeno Tn quede expuesto al sistema inmune generando una respuesta inmunológica. Desde el punto de vista estructural, el antígeno Tn está formado por Nacetilgalactosamina (GalNAc) unida mediante un enlace -O-gliosídico a serina (Ser) o treonina (Thr), sin especificar a qué aminoácido se une el GalNAc. Sin embargo, en esta tesis hemos sintetizado diferentes epítopos representativos de MUC1 que incorporan Ser y Thr en su estructura. Hemos analizado las interacciones que ocurren en el reconocimiento de GalNAc por diferentes lectinas, observando que es importante especificar a qué aminoácido se une el residuo carbohidrato GalNAc. También hemos analizado la importancia de los aminoácidos que rodean al antígeno Tn en la cadena peptídica, obteniendo resultados sorprendentes en términos de afinidad a lectinas. Además, hemos obtenido por primera vez, una estructura de rayos X de la lectina soybean agglutinin (SBA) unida a un glycopéptido derivado de la mucina humana MUC1. Todos estos resultados podrían tener importantes implicaciones para entender mejor las interacciones glicopéptido-lectina y podría contribuir al diseño y construción de nuevos sitios de unión, permitiendo el diseño de nuevos glicosensores para la detección de antígeno Tn en células tumoralesUniversidad de La Rioja (España)Peregrina García, Jesús Manuel (Universidad de La Rioja)Corzana López, Francisco (Universidad de La Rioja)2015text (thesis)application/pdfhttps://dialnet.unirioja.es/servlet/oaites?codigo=44390engLICENCIA DE USO: Los documentos a texto completo incluidos en Dialnet son de acceso libre y propiedad de sus autores y/o editores. Por tanto, cualquier acto de reproducción, distribución, comunicación pública y/o transformación total o parcial requiere el consentimiento expreso y escrito de aquéllos. Cualquier enlace al texto completo de estos documentos deberá hacerse a través de la URL oficial de éstos en Dialnet. 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