{"doi":"10.1126/sciadv.adq7560","title":"Structural basis of aquaporin-4 autoantibody binding in neuromyelitis optica","abstract":"Neuromyelitis optica (NMO) is an autoimmune disease of the central nervous system where pathogenic autoantibodies target the water channel aquaporin-4 on human astrocytes causing neurological impairment. Autoantibody binding leads to complement-dependent and complement-independent cytotoxicity, ultimately resulting in astrocyte death, demyelination, and neuronal loss. Aquaporin-4 assembles in astrocyte plasma membranes as symmetric tetramers or as arrays of tetramers. We report molecular structures of aquaporin-4 alone and bound to Fab fragments from patient-derived NMO autoantibodies using cryogenic electron microscopy. Each antibody binds to epitopes comprised of three extracellular loops of aquaporin-4 with contributions from multiple molecules in the assembly. The structures distinguish between antibodies that bind to the tetrameric form of aquaporin-4 and those targeting higher-order orthogonal arrays of tetramers that provide more diverse bridging epitopes.","journal":"Science Advances","year":2025,"id":516480,"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":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9602,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":774662,"name":"Nitesh Khandelwal","orcid":"0000-0002-6319-8048","position":1,"is_corresponding":false},{"id":1187856,"name":"Andrew Nelson","orcid":"0000-0001-6665-4929","position":2,"is_corresponding":false},{"id":1382270,"name":"Peter Hwang","orcid":null,"position":3,"is_corresponding":false},{"id":108110,"name":"Sergei Pourmal","orcid":"0000-0002-7537-6016","position":4,"is_corresponding":false},{"id":226913,"name":"Jeffrey L. Bennett","orcid":"0000-0002-3346-1394","position":5,"is_corresponding":false},{"id":103698,"name":"Robert M. Stroud","orcid":"0000-0003-2083-5665","position":6,"is_corresponding":false},{"id":108109,"name":"Meghna Gupta","orcid":"0000-0002-7432-3211","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-19T02:48:49.486328Z","pmid":"39982991","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":[]}