{"doi":"10.1101/2023.11.05.565221","title":"Evolutionary origin and structural ligand mimicry by the inserted domain of alpha-integrin proteins","abstract":"Heterodimeric integrin proteins transmit signals through conformational changes upon ligand binding between their alpha (α) and beta (β) subunits. Early in chordate evolution, some α subunits acquired an \"inserted\" (I) domain, which expanded their ligand binding capacity but simultaneously obstructed the ancestral ligand-binding pocket. While this would seemingly impede conventional ligand-mediated integrin activation, it was proposed that the I domain itself could serve both as a ligand replacement and an activation trigger. Here, we provide compelling evidence in support of this longstanding hypothesis using high-resolution cryo-electron microscopy structures of two distinct integrin complexes: the ligand-free and E-cadherin-bound states of the αEβ7 integrin with the I domain, as well as the α4β7 integrin lacking the I domain in both a ligand-free state and bound to MadCAM-1. We trace the evolutionary origin of the I domain to an ancestral collagen-collagen interaction domain. Our analyses illuminate how the I domain intrinsically mimics an extrinsic ligand, enabling integrins to undergo the canonical allosteric cascade of conformational activation and dramatically expanding the range of cellular communication mechanisms in vertebrates.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":401465,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.948,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":815481,"name":"Matthew C. Chan","orcid":"0000-0002-9826-1983","position":1,"is_corresponding":false},{"id":341208,"name":"Harmit S. Malik","orcid":"0000-0001-6005-0016","position":2,"is_corresponding":false},{"id":108121,"name":"Melody G. Campbell","orcid":"0000-0003-1909-5751","position":3,"is_corresponding":false},{"id":458498,"name":"Jeremy A. Hollis","orcid":"0000-0003-3375-8937","position":0,"is_corresponding":true}],"reference_count":95,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:20:12.316631Z","pmid":"37986796","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":[]}