An unusual dual sugar-binding lectin domain controls the substrate specificity of a mucin-type O-glycosyltransferase.

Publication date: Mar 01, 2024

N-acetylgalactosaminyl-transferases (GalNAc-Ts) initiate mucin-type O-glycosylation, an abundant and complex posttranslational modification that regulates host-microbe interactions, tissue development, and metabolism. GalNAc-Ts contain a lectin domain consisting of three homologous repeats (α, β, and γ), where α and β can potentially interact with O-GalNAc on substrates to enhance activity toward a nearby acceptor Thr/Ser. The ubiquitous isoenzyme GalNAc-T1 modulates heart development, immunity, and SARS-CoV-2 infectivity, but its substrates are largely unknown. Here, we show that both α and β in GalNAc-T1 uniquely orchestrate the O-glycosylation of various glycopeptide substrates. The α repeat directs O-glycosylation to acceptor sites carboxyl-terminal to an existing GalNAc, while the β repeat directs O-glycosylation to amino-terminal sites. In addition, GalNAc-T1 incorporates α and β into various substrate binding modes to cooperatively increase the specificity toward an acceptor site located between two existing O-glycans. Our studies highlight a unique mechanism by which dual lectin repeats expand substrate specificity and provide crucial information for identifying the biological substrates of GalNAc-T1.

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Concepts Keywords
Glycosyltransferase Acceptor
Host Binding
Posttranslational Domain
Sugar Dual
Unknown Galnac
Glycosylation
Lectin
Mucin
Specificity
Substrate
Substrates
T1
Ts
Type

Semantics

Type Source Name
disease IDO host
pathway REACTOME Metabolism
drug DRUGBANK L-Threonine
drug DRUGBANK Serine
disease IDO infectivity
disease IDO site

Original Article

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