{"doi":"10.1016/j.mcpro.2024.100747","title":"Galectin-4 Antimicrobial Activity Primarily Occurs Through its C-Terminal Domain","abstract":"Although immune tolerance evolved to reduce reactivity with self, it creates a gap in the adaptive immune response against microbes that decorate themselves in self-like antigens. This is particularly apparent with carbohydrate-based blood group antigens, wherein microbes can envelope themselves in blood group structures similar to human cells. In this study, we demonstrate that the innate immune lectin, galectin-4 (Gal-4), exhibits strain-specific binding and killing behavior towards microbes that display blood group-like antigens. Examination of binding preferences using a combination of microarrays populated with ABO(H) glycans and a variety of microbial strains, including those that express blood group-like antigens, demonstrated that Gal-4 binds mammalian and microbial antigens that have features of blood group and mammalian-like structures. Although Gal-4 was thought to exist as a monomer that achieves functional bivalency through its two linked carbohydrate recognition domains, our data demonstrate that Gal-4 forms dimers and that differences in the intrinsic ability of each domain to dimerize likely influences binding affinity. While each Gal-4 domain exhibited blood group-binding activity, the C-terminal domain (Gal-4C) exhibited dimeric properties, while the N-terminal domain (Gal-4N) failed to similarly display dimeric activity. Gal-4C not only exhibited the ability to dimerize but also possessed higher affinity toward ABO(H) blood group antigens and microbes expressing glycans with blood group-like features. Furthermore, when compared to Gal-4N, Gal-4C exhibited more potent antimicrobial activity. Even in the context of the full-length protein, where Gal-4N is functionally bivalent by virtue of Gal-4C dimerization, Gal-4C continued to display higher antimicrobial activity. These results demonstrate that Gal-4 exists as a dimer and exhibits its antimicrobial activity primarily through its C-terminal domain. In doing so, these data provide important insight into key features of Gal-4 responsible for its innate immune activity against molecular mimicry.","journal":"Molecular & Cellular Proteomics","year":2024,"id":433770,"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":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9513,"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":693546,"name":"Shang‐Chuen Wu","orcid":"0000-0002-5284-5596","position":1,"is_corresponding":false},{"id":1071169,"name":"Carter J. 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Lane","orcid":"0000-0002-1097-5229","position":14,"is_corresponding":false},{"id":473193,"name":"Melissa Y. Yeung","orcid":"0000-0002-1130-3192","position":15,"is_corresponding":false},{"id":853186,"name":"Marie A. Hollenhorst","orcid":"0000-0002-2237-6645","position":16,"is_corresponding":false},{"id":573788,"name":"Seth Rakoff-Nahoum","orcid":"0000-0002-3233-0675","position":17,"is_corresponding":false},{"id":231529,"name":"Richard D. Cummings","orcid":"0000-0002-8918-5034","position":18,"is_corresponding":false},{"id":226163,"name":"Connie M. Arthur","orcid":"0009-0006-9246-7231","position":19,"is_corresponding":false},{"id":226169,"name":"Sean R. 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