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Deciphering the Non‐Equivalence of Serine and Threonine O‐Glycosylation Points: Implications for Molecular Recognition of the Tn Antigen by an anti‐MUC1 Antibody |
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| Authors: | Dr Nuria Martínez‐Sáez Jorge Castro‐López Jessika Valero‐González Dr David Madariaga Ismael Compañón Dr Víctor J Somovilla Míriam Salvadó Dr Juan L Asensio Dr Jesús Jiménez‐Barbero Dr Alberto Avenoza Dr Jesús H Busto Dr Gonçalo J L Bernardes Dr Jesús M Peregrina Dr Ramón Hurtado‐Guerrero Dr Francisco Corzana |
| Institution: | 1. Departamento de Química, Universidad de La Rioja, Centro de Investigación en Síntesis Química, 26006 Logro?o (Spain);2. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW (UK);3. Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, BIFI‐IQFR (CSIC) Joint Unit, Edificio I+D, 50018 Zaragoza (Spain);4. Fundación ARAID, Edificio Pignatelli 36, Zaragoza (Spain);5. Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili, C/Marcellí Domingo s/n, 43007 Tarragona (Spain);6. Instituto de Química Orgánica General, IQOG‐CSIC, Juan de la Cierva 3, 28006 Madrid (Spain);7. Structural Biology Unit, CIC bioGUNE, Parque Tecnológico de Bizkaia Building 801?A, 48160 Derio (Spain);8. IKERBASQUE, Basque Foundation for Science, 48011 Bilbao (Spain);9. Department of Chemical and Physical Biology, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28040 Madrid (Spain);10. Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, 1649‐028 Lisboa (Portugal) |
| Abstract: | The structural features of MUC1‐like glycopeptides bearing the Tn antigen (α‐O‐GalNAc‐Ser/Thr) in complex with an anti MUC‐1 antibody are reported at atomic resolution. For the α‐O‐GalNAc‐Ser derivative, the glycosidic linkage adopts a high‐energy conformation, barely populated in the free state. This unusual structure (also observed in an α‐S‐GalNAc‐Cys mimic) is stabilized by hydrogen bonds between the peptidic fragment and the sugar. The selection of a particular peptide structure by the antibody is thus propagated to the carbohydrate through carbohydrate/peptide contacts, which force a change in the orientation of the sugar moiety. This seems to be unfeasible in the α‐O‐GalNAc‐Thr glycopeptide owing to the more limited flexibility of the side chain imposed by the methyl group. Our data demonstrate the non‐equivalence of Ser and Thr O‐glycosylation points in molecular recognition processes. These features provide insight into the occurrence in nature of the APDTRP epitope for anti‐MUC1 antibodies. |
| Keywords: | antibodies conformation analysis glycopeptides molecular recognition X‐ray diffraction |