New insights into molecular recognition of epitopes related to MUC1 human mucin by lectins

  1. Madariaga Merino, David
unter der Leitung von:
  1. Jesús Manuel Peregrina García Doktorvater/Doktormutter
  2. Francisco Corzana López Doktorvater/Doktormutter

Universität der Verteidigung: Universidad de La Rioja

Fecha de defensa: 28 von Januar von 2015

Gericht:
  1. Jesús Jiménez Barbero Präsident/in
  2. Filipa Marcelo Sekretär/in
  3. José Luis Mascareñas Cid Vocal

Art: Dissertation

Zusammenfassung

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.