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bioRxiv · 10.1101/2024.05.12.592631

Structural basis of autoantibody binding in Neuromyelitis Optica

Gupta, M.·Khandelwal, N. K.·Nelson, A.·Hwang, P.·Pourmal, S.·Bennett, J. L.·Stroud, R. M.
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Abstract

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. One-Sentence SummaryPathogenic autoantibodies in Neuromyelitis Optica distinguish multiply presented epitopes on arrays of human aquaporin-4.

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Gupta, M., Khandelwal, N. K., Nelson, A., Hwang, P., Pourmal, S., Bennett, J. L., Stroud, R. M.. 2024-05-14. Structural basis of autoantibody binding in Neuromyelitis Optica. https://doi.org/10.1101/2024.05.12.592631

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