Site-Specific Conformational Alteration Induced by Sialylation of MUC1 Tandem Repeating Glycopeptides at an Epitope Region for the Anti-KL-6 Monoclonal Antibody

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• 作者：Takahiko Matsushita ; Naoki Ohyabu ; Naoki Fujitani ; Kentaro Naruchi ; Hiroki Shimizu ; Hiroshi Hinou ; Shin-Ichiro Nishimura
• 刊名：Biochemistry
• 出版年：2013
• 出版时间：January 15, 2013
• 年：2013
• 卷：52
• 期：2
• 页码：402-414
• 全文大小：508K
• 年卷期：v.52,no.2(January 15, 2013)
• ISSN：1520-4995

文摘

Protein O-glycosylation is an essential step for controlling structure and biological functions of glycoproteins involving differentiation, cell adhesion, immune response, inflammation, and tumorigenesis and metastasis. This study provides evidence of site-specific structural alteration induced during multiple sialylation at Ser/Thr residues of the tandem repeats in human MUC1 glycoprotein. Systematic nuclear magnetic resonance (NMR) study revealed that sialylation of the MUC1 tandem repeating glycopeptide, Pro-Pro-Ala-His-Gly-Val-Thr-Ser-Ala-Pro-Asp-Thr-Arg-Pro-Ala-Pro-Gly-Ser-Thr-Ala with core 2-type O-glycans at five potential glycosylation sites, afforded a specific conformational change at one of the most important cancer-relevant epitopes (Pro-Asp-Thr-Arg). This result indicates that disease-relevant epitope structures of human epithelial cell surface mucins can be altered both by the introduction of an inner GalNAc residue and by the distal sialylation in a peptide sequence-dependent manner. These data demonstrate the feasibility of NMR-based structural characterization of glycopeptides synthesized in a chemical and enzymatic manner in examining the conformational impact of the distal glycosylation at multiple O-glycosylation sites of mucin-like domains.