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Remote Activation of a Latent Epitope in an Autoantigen Decoded with Simulated B-Factors

View ORCID ProfileYuan-Ping Pang, View ORCID ProfileMarta Casal Moura, View ORCID ProfileGwen E. Thompson, View ORCID ProfileDarlene R. Nelson, Amber M. Hummel, View ORCID ProfileDieter E. Jenne, Daniel Emerling, View ORCID ProfileWayne Volkmuth, View ORCID ProfileWilliam H. Robinson, View ORCID ProfileUlrich Specks
doi: https://doi.org/10.1101/559963
Yuan-Ping Pang
1Computer-Aided Molecular Design Laboratory, Mayo Clinic, Rochester, MN, USA
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  • For correspondence: pang@mayo.edu specks.ulrich@mayo.edu
Marta Casal Moura
2Thoracic Disease Research Unit, Mayo Clinic, Rochester, MN, USA
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Gwen E. Thompson
2Thoracic Disease Research Unit, Mayo Clinic, Rochester, MN, USA
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Darlene R. Nelson
2Thoracic Disease Research Unit, Mayo Clinic, Rochester, MN, USA
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Amber M. Hummel
2Thoracic Disease Research Unit, Mayo Clinic, Rochester, MN, USA
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Dieter E. Jenne
3Institute of Lung Biology and Disease, Helmholtz-Center, Munich, Germany
4Max Planck Institute of Neurobiology, Planegg-Martinsried, Germany
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Daniel Emerling
5Atreca, Inc., Redwood City, CA, USA
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Wayne Volkmuth
5Atreca, Inc., Redwood City, CA, USA
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William H. Robinson
6Stanford University, Palo Alto, CA, USA
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Ulrich Specks
2Thoracic Disease Research Unit, Mayo Clinic, Rochester, MN, USA
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  • For correspondence: pang@mayo.edu specks.ulrich@mayo.edu
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Abstract

Mutants of a catalytically inactive variant of Proteinase 3 (PR3)—iPR3-Val103 possessing a Ser195Ala mutation relative to wild-type PR3-Val103—offer insights into how autoantigen PR3 interacts with antineutrophil cytoplasmic antibodies (ANCAs) in granulomatosis with polyangiitis (GPA) and whether such interactions can be interrupted. Here we report that iHm5-Val103, a triple mutant of iPR3-Val103, bound a monoclonal antibody (moANCA518) from a GPA patient on an epitope remote from the mutation sites, whereas the corresponding epitope of iPR3-Val103 was latent to moANCA518. Simulated B-factor analysis revealed that the binding of moANCA518 to iHm5-Val103 was due to increased main-chain flexibility of the latent epitope caused by remote mutations, suggesting rigidification of epitopes with therapeutics to alter pathogenic PR3•ANCA interactions as new GPA treatments.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted September 27, 2019.
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Remote Activation of a Latent Epitope in an Autoantigen Decoded with Simulated B-Factors
Yuan-Ping Pang, Marta Casal Moura, Gwen E. Thompson, Darlene R. Nelson, Amber M. Hummel, Dieter E. Jenne, Daniel Emerling, Wayne Volkmuth, William H. Robinson, Ulrich Specks
bioRxiv 559963; doi: https://doi.org/10.1101/559963
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Remote Activation of a Latent Epitope in an Autoantigen Decoded with Simulated B-Factors
Yuan-Ping Pang, Marta Casal Moura, Gwen E. Thompson, Darlene R. Nelson, Amber M. Hummel, Dieter E. Jenne, Daniel Emerling, Wayne Volkmuth, William H. Robinson, Ulrich Specks
bioRxiv 559963; doi: https://doi.org/10.1101/559963

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