{"doi":"10.4049/jimmunol.0901141","title":"MASP-1, a Promiscuous Complement Protease: Structure of Its Catalytic Region Reveals the Basis of Its Broad Specificity","abstract":"<jats:title>Abstract</jats:title>\n                  <jats:p>Mannose-binding lectin (MBL)-associated serine protease (MASP)-1 is an abundant component of the lectin pathway of complement. The related enzyme, MASP-2 is capable of activating the complement cascade alone. Though the concentration of MASP-1 far exceeds that of MASP-2, only a supporting role of MASP-1 has been identified regarding lectin pathway activation. Several non-complement substrates, like fibrinogen and factor XIII, have also been reported. MASP-1 belongs to the C1r/C1s/MASP family of modular serine proteases; however, its serine protease domain is evolutionary different. We have determined the crystal structure of the catalytic region of active MASP-1 and refined it to 2.55 Å resolution. Unusual features of the structure are an internal salt bridge (similar to one in factor D) between the S1 Asp189 and Arg224, and a very long 60-loop. The functional and evolutionary differences between MASP-1 and the other members of the C1r/C1s/MASP family are reflected in the crystal structure. Structural comparison of the protease domains revealed that the substrate binding groove of MASP-1 is wide and resembles that of trypsin rather than early complement proteases explaining its relaxed specificity. Also, MASP-1’s multifunctional behavior as both a complement and a coagulation enzyme is in accordance with our observation that antithrombin in the presence of heparin is a more potent inhibitor of MASP-1 than C1 inhibitor. Overall, MASP-1 behaves as a promiscuous protease. The structure shows that its substrate binding groove is accessible; however, its reactivity could be modulated by an unusually large 60-loop and an internal salt bridge involving the S1 Asp.</jats:p>","journal":"The Journal of Immunology","year":2009,"id":17502,"datarank":3.332538837217964,"base_score":4.804021044733257,"endowment":4.804021044733257,"self_citation_contribution":0.7206031567099886,"citation_network_contribution":2.611935680507975,"self_endowment_contribution":0.7206031567099886,"citer_contribution":2.611935680507975,"corpus_percentile":null,"corpus_rank":null,"citation_count":121,"citer_count":74,"citers_with_citation_signal":63,"citers_with_endowment":63,"datacite_reuse_total":1,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":124995,"name":"Veronika Harmat","orcid":null,"position":1,"is_corresponding":false},{"id":124996,"name":"László Beinrohr","orcid":null,"position":2,"is_corresponding":false},{"id":124997,"name":"Edina Sebestyén","orcid":null,"position":3,"is_corresponding":false},{"id":122886,"name":"Péter Závodszky","orcid":null,"position":4,"is_corresponding":false},{"id":122888,"name":"Péter Gál","orcid":null,"position":5,"is_corresponding":false},{"id":122890,"name":"József Dobó","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":4.804021044733257,"endowment":4.804021044733257,"datacite_reuse_total":1,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19564340","pmcid":null,"openalex_id":"https://openalex.org/W1574595419","authors":[],"funders":[],"total_grants":0,"fwci":3.4415,"citation_percentile":0.92640641,"influential_citations":1,"citation_trend":[{"year":2012,"count":9},{"year":2013,"count":9},{"year":2014,"count":5},{"year":2015,"count":8},{"year":2016,"count":7},{"year":2017,"count":10},{"year":2018,"count":10},{"year":2019,"count":8},{"year":2020,"count":7},{"year":2021,"count":7},{"year":2022,"count":10},{"year":2023,"count":5},{"year":2024,"count":4},{"year":2025,"count":2},{"year":2026,"count":1}],"oa_status":"bronze","license":"https://academic.oup.com/pages/standard-publication-reuse-rights","oa_locations":[{"url":"https://www.jimmunol.org/content/jimmunol/183/2/1207.full.pdf","host_type":"journal"},{"url":"https://www.jimmunol.org/content/jimmunol/183/2/1207.full.pdf","host_type":"BRONZE"},{"url":"https://www.jimmunol.org/content/jimmunol/183/2/1207.full.pdf","host_type":"publisher"},{"url":"https://academic.oup.com/jimmunol/article-pdf/183/2/1207/62696747/9354.pdf","host_type":"publisher"},{"url":"https://doi.org/10.4049/jimmunol.0901141","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/19564340","host_type":"repository"},{"url":"https://bib-pubdb1.desy.de/record/92827","host_type":"repository"},{"url":"https://doi.org/10.3204/phppubdb-11946","host_type":"repository"},{"url":"https://bib-pubdb1.desy.de/search?p=id:%22PHPPUBDB-11946%22","host_type":"repository"}],"fields_of_study":["Complement system in diseases","Coagulation, Bradykinin, Polyphosphates, and Angioedema","Blood Coagulation and Thrombosis Mechanisms","Medicine","Biology","Chemistry","Antithrombin III","Catalytic Domain","Crystallography, X-Ray","Evolution, Molecular","Heparin","Humans","Mannose-Binding Protein-Associated Serine Proteases","Peptide Fragments","Protein Conformation","Recombinant Proteins","Serine Endopeptidases","Static Electricity","Substrate Specificity"],"mesh_terms":["Antithrombin III","Heparin","Humans","Peptide Fragments","Protein Conformation","Recombinant Proteins","Serine Endopeptidases","Substrate Specificity","Crystallography, X-Ray","Evolution, Molecular","Catalytic Domain","Mannose-Binding Protein-Associated Serine Proteases","Static Electricity"],"keywords":["MASP1","Lectin pathway","Mannan-binding lectin","Serine protease","Ficolin","Complement system","Proteases","Chemistry","Complement control protein","Protease","Complement component 2","Biochemistry","Factor H","Lectin","Biology","Classical complement pathway","Enzyme","Genetics"],"sdg_mappings":[],"linked_datasets":[{"doi":"10.3204/phppubdb-11946","title":"MASP-1, a Promiscuous Complement Protease: Structure of Its Catalytic Region Reveals the Basis of Its Broad Specificity","publisher":"Deutsches Elektronen-Synchrotron, DESY, Hamburg","resource_type":"Text"}],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-06-02T19:10:49.199638Z","pmid":null,"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":[]}