Redox-dependent plasticity of oxMIF facilitates its interaction with CD74 and therapeutic antibodies.
Redox Biol
; 75: 103264, 2024 Sep.
Article
em En
| MEDLINE
| ID: mdl-38972295
ABSTRACT
MIF is a ubiquitous protein involved in proinflammatory processes, which undergoes an oxidation-driven conformational change to oxidized (ox)MIF. We demonstrate that hypochlorous acid, produced by neutrophil-released myeloperoxidase (MPO) under inflammatory conditions, effectively oxidizes MIF into the oxMIF isoform, which is specifically recognized by the anti-oxMIF therapeutic antibody, ON104. NMR investigation of MIF oxidized by the MPO system revealed increased flexibility throughout the MIF structure, including at several catalytic and allosteric sites. Mass spectrometry of MPO-oxMIF revealed methionines as the primary site of oxidation, whereas Pro2 and Tyr99/100 remained almost unmodified. ELISA, SPR and cell-based assays demonstrated that structural changes caused by MPO-driven oxidation promoted binding of oxMIF to its receptor, CD74, which does not occur with native MIF. These data reveal the environment and modifications that facilitate interactions between MIF and its pro-inflammatory receptor, and a route for therapeutic intervention targeting the oxMIF isoform.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Oxirredução
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Ligação Proteica
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Antígenos de Diferenciação de Linfócitos B
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Antígenos de Histocompatibilidade Classe II
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Fatores Inibidores da Migração de Macrófagos
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Oxirredutases Intramoleculares
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article