ArticlebioRxiv : the preprint server for biology2024
Structural Basis of Aquaporin-4 Autoantibody Binding in Neuromyelitis Optica.
Meghna Gupta, Nitesh Kumar Khandelwal, Andrew Nelson, Peter Hwang, Sergei Pourmal, Jeffrey L Bennett, Robert M Stroud
Abstract readPreprint
In one paragraphArticle in bioRxiv : the preprint server for biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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5 · Who and what moneyAuthors and funding
7 authors.
Meghna GuptaDepartment of Biochemistry and Biophysics, University of California San Francisco; San Francisco, CA 94143, USA.ORCID 0000-0002-7432-3211 Nitesh Kumar KhandelwalDepartment of Biochemistry and Biophysics, University of California San Francisco; San Francisco, CA 94143, USA.ORCID 0000-0002-6319-8048 Andrew NelsonDepartment of Biochemistry and Biophysics, University of California San Francisco; San Francisco, CA 94143, USA.
Peter HwangDepartment of Biochemistry and Biophysics, University of California San Francisco; San Francisco, CA 94143, USA.
Sergei PourmalDepartment of Biochemistry and Biophysics, University of California San Francisco; San Francisco, CA 94143, USA.
Jeffrey L BennettDepartments of Neurology and Ophthalmology, Programs in Neuroscience and Immunology, University of Colorado School of Medicine, Anschutz Medical Campus; Aurora, CO 80045, USA.
Robert M StroudDepartment of Biochemistry and Biophysics, University of California San Francisco; San Francisco, CA 94143, USA.ORCID 0000-0003-2083-5665 Funding
STRUCTURE/FUNCTION OF PROTEINS AT MOLECULAR LEVELR01GM024485 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI STROUD, ROBERT M · 1985 to 2024
$7.5MHumoral Immunity, Astrocyte Injury, and Demyelination in Neuromyelitis OpticaR01EY022936 · NEI · UNIVERSITY OF COLORADO DENVER · PI BENNETT, JEFFREY L · 2013 to 2022
$3.8MAcquisition of an electron microscope for high-resolution single particle cryo-EMS10OD021741 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHENG, YIFAN · 2016 to 2016
$2.0MGlacios™ Cryo Transmission Electron Microscope with 200 kV XFEG opticsS10OD026881 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHENG, YIFAN · 2019 to 2019
$1.8MMolecular Basis for Transmembrane Conduction & SignalingR35GM156263 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Robert M Stroud · 2025 to 2026
$1.2MLinux cluster for near atomic resolution single particle cryo-EMS10OD020054 · OD · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHENG, YIFAN · 2015 to 2015
$456kPeroxisomal fatty acid metabolism in genetic and age-related disordersK99AG070271 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI GUPTA, MEGHNA · 2022 to 2023
$250kNEI NIH HHS R01 EY022936NIA NIH HHS K99 AG070271NIGMS NIH HHS R01 GM024485NIGMS NIH HHS R35 GM156263NIH HHS S10 OD020054NIH HHS S10 OD021741NIH HHS S10 OD026881
6 · The paper itselfAbstract
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.
Identifiers
PMID38798537
PMCPMC11118524
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