UDP-GalNAc : Polypeptide N-acetylgalactosaminyltransferase 1 (GalNAc-T1) の構造活性相関 : GalNAc-T1のレクチン様ドメインの機能解析

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  • Structure-function Relationship of UDP-GalNAc : Polypeptide N-acetylgalactosaminyltransferase 1 (GalNAc-T1) : Function of the Lectin Domain of GalNAc-T1

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The initial step of mucin-type O-glycosylation is catalyzed by UDP-GalNAc : polypeptide N-acetylgalactosaminyltransferases (GalNAc-transferases). GalNAc-transferases contain a lectin domain at the C-terminus, consisting of three tandem repeats (α, β, and γ). I have reevaluated the role of the GalNAc-T1 lectin domain in this study, because the putative lectin domain of this enzyme is reportedly not functional. Deletion of the lectin domain resulted in a complete loss of enzymatic activity. I found that GalNAc-T1 has two activities distinguished by their sensitivities to inhibition with free GalNAc; one activity is sensitive, the other is resistant. In my experiments, the former activity is represented by the O-glycosylation of apomucin, an acceptor that contains multiple glycosylation sites, and the latter by synthetic peptides that contain a single glycosylation site. Site-directed mutagenesis of the lectin domain selectively reduced the follow-up activity, and identified Asp444 in the α repeat as the most important site for GalNAc recognition. I also found that the β repeat recognizes GalNAc and is involved in glycosylation of acceptors with multiple glycosylation sites. These results indicate that the lectin domain of GalNAc-T1 has at least two functional repeats, allowing the possibility of multivalent interactions with GalNAc residues on the acceptor peptide during glycosylation.

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