{"doi":"10.1126/sciadv.adj8829","title":"An unusual dual sugar-binding lectin domain controls the substrate specificity of a mucin-type O-glycosyltransferase","abstract":"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.","journal":"Science Advances","year":2024,"id":431431,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":439444,"name":"Sergio A. Hassan","orcid":"0000-0003-3319-078X","position":1,"is_corresponding":false},{"id":1235261,"name":"S SCHMIDT","orcid":"0000-0001-5214-2340","position":2,"is_corresponding":false},{"id":1067488,"name":"Alexander J. Lara","orcid":"0000-0002-3781-9584","position":3,"is_corresponding":false},{"id":479586,"name":"Weiming Yang","orcid":"0000-0002-5023-2155","position":4,"is_corresponding":false},{"id":432038,"name":"N.L. Samara","orcid":"0000-0001-7152-2939","position":5,"is_corresponding":false},{"id":1235260,"name":"Abbie M. Collette","orcid":"0009-0009-4298-7732","position":0,"is_corresponding":true}],"reference_count":69,"raw_metadata":null,"created_at":"2026-07-19T01:59:25.642507Z","pmid":"38416819","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}