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Structures of proteinase 3 and the CD177 receptor complex reveal a major autoantibody epitope

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Structures of proteinase 3 and the CD177 receptor complex reveal a major autoantibody epitope
Συγγραφείς: Zheng-Gérard, C, Joha, J, Carrasquero, M, El Omari, K, Lowe, E, Dubey, S, Draper, SJ, Chang, Y-C, Lin, H-H, Salama, AD, McHugh, K, Seiradake, E
Στοιχεία εκδότη: Springer Nature
Έτος έκδοσης: 2026
Συλλογή: Oxford University Research Archive (ORA)
Περιγραφή: Granulomatosis with polyangiitis is a life-threatening systemic vasculitis, characterised by anti-neutrophil cytoplasmic autoantibodies (ANCA) most commonly against proteinase 3 (PR3), a protease expressed intracellularly and on the surface of neutrophils. Most cell surface PR3 is bound to the receptor CD177; however, the molecular mechanism of the interactions is not well understood. Here, we present crystal structures of CD177 in complex with PR3 and unliganded CD177. We describe a mainly hydrophobic binding interface between PR3 and CD177, involving the first two Ly6/uPAR (LU) domains of CD177. These form a globular structure which is connected to downstream domains via a flexible linker. Using a panel of PR3-ANCA-positive patient samples, we show that a significant proportion of ANCAs target the CD177-binding site of PR3 in these samples. Structure-guided mutation of the CD177-binding site on PR3 is effective in reducing PR3-ANCA binding. The results demonstrate that the CD177-binding surface of PR3 harbours a major PR3-ANCA epitope, and that the extent of binding to this surface varies between different patients.
Τύπος εγγράφου: article in journal/newspaper
Γλώσσα: English
DOI: 10.1038/s44319-026-00716-5
Διαθεσιμότητα: https://doi.org/10.1038/s44319-026-00716-5
https://ora.ox.ac.uk/objects/uuid:85fa0e6b-2634-4608-b4ef-f1cb5a923585
Rights: info:eu-repo/semantics/openAccess ; CC Attribution (CC BY)
Αριθμός Καταχώρησης: edsbas.1FC085DF
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  – Url: https://doi.org/10.1038/s44319-026-00716-5#
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  Data: Structures of proteinase 3 and the CD177 receptor complex reveal a major autoantibody epitope
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  Data: <searchLink fieldCode="AR" term="%22Zheng-Gérard%2C+C%22">Zheng-Gérard, C</searchLink><br /><searchLink fieldCode="AR" term="%22Joha%2C+J%22">Joha, J</searchLink><br /><searchLink fieldCode="AR" term="%22Carrasquero%2C+M%22">Carrasquero, M</searchLink><br /><searchLink fieldCode="AR" term="%22El+Omari%2C+K%22">El Omari, K</searchLink><br /><searchLink fieldCode="AR" term="%22Lowe%2C+E%22">Lowe, E</searchLink><br /><searchLink fieldCode="AR" term="%22Dubey%2C+S%22">Dubey, S</searchLink><br /><searchLink fieldCode="AR" term="%22Draper%2C+SJ%22">Draper, SJ</searchLink><br /><searchLink fieldCode="AR" term="%22Chang%2C+Y-C%22">Chang, Y-C</searchLink><br /><searchLink fieldCode="AR" term="%22Lin%2C+H-H%22">Lin, H-H</searchLink><br /><searchLink fieldCode="AR" term="%22Salama%2C+AD%22">Salama, AD</searchLink><br /><searchLink fieldCode="AR" term="%22McHugh%2C+K%22">McHugh, K</searchLink><br /><searchLink fieldCode="AR" term="%22Seiradake%2C+E%22">Seiradake, E</searchLink>
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  Data: 2026
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  Data: Granulomatosis with polyangiitis is a life-threatening systemic vasculitis, characterised by anti-neutrophil cytoplasmic autoantibodies (ANCA) most commonly against proteinase 3 (PR3), a protease expressed intracellularly and on the surface of neutrophils. Most cell surface PR3 is bound to the receptor CD177; however, the molecular mechanism of the interactions is not well understood. Here, we present crystal structures of CD177 in complex with PR3 and unliganded CD177. We describe a mainly hydrophobic binding interface between PR3 and CD177, involving the first two Ly6/uPAR (LU) domains of CD177. These form a globular structure which is connected to downstream domains via a flexible linker. Using a panel of PR3-ANCA-positive patient samples, we show that a significant proportion of ANCAs target the CD177-binding site of PR3 in these samples. Structure-guided mutation of the CD177-binding site on PR3 is effective in reducing PR3-ANCA binding. The results demonstrate that the CD177-binding surface of PR3 harbours a major PR3-ANCA epitope, and that the extent of binding to this surface varies between different patients.
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  Data: 10.1038/s44319-026-00716-5
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