biostudies-literatureUnknownGupta MNEI NIH HHSNIA NIH HHSNIH HHSNIGMS NIH HHSNeuromyelitis Optica (NMO) is an autoimmune disease of the central nervous system where pathogenic autoantibodies target the human astrocyte water channel aquaporin-4 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.bioRxiv : the preprint server for biology2024.05.12.592631https://www.ebi.ac.uk/biostudies/studies/S-EPMC11118524biostudies-literatureStructural Basis of Aquaporin-4 Autoantibody Binding in Neuromyelitis Optica.PMC11118524K99 AG070271S10 OD020054S10 OD026881R01 GM024485R01 EY022936S10 OD021741Hwang PStroud RMNelson APourmal SKhandelwal NKGupta MBennett JLfalseStructural Basis of Aquaporin-4 Autoantibody Binding in Neuromyelitis Optica.Neuromyelitis Optica (NMO) is an autoimmune disease of the central nervous system where pathogenic autoantibodies target the human astrocyte water channel aquaporin-4 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.2024-01-01T00:00:00Z2024 May2026-04-13T03:27:11.995Z2026-04-13T03:12:59.499ZS-EPMC111185243879853710.1101/2024.05.12.592631