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“Conformational dynamics of C1r inhibitor proteins from Lyme disease and relapsing fever spirochetes”

Borrelial pathogens are vector-borne etiological agents of Lyme disease, relapsing fever, and Borrelia miyamotoi disease. These spirochetes each encode several surface-localized lipoproteins that bind to components of the human complement system. BBK32 is an example of a borrelial lipoprotein that p...

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Autores principales: Roy, Sourav, Booth, Charles E., Powell-Pierce, Alexandra D., Schulz, Anna M., Skare, Jon T., Garcia, Brandon L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10002728/
https://www.ncbi.nlm.nih.gov/pubmed/36909632
http://dx.doi.org/10.1101/2023.03.01.530473
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author Roy, Sourav
Booth, Charles E.
Powell-Pierce, Alexandra D.
Schulz, Anna M.
Skare, Jon T.
Garcia, Brandon L.
author_facet Roy, Sourav
Booth, Charles E.
Powell-Pierce, Alexandra D.
Schulz, Anna M.
Skare, Jon T.
Garcia, Brandon L.
author_sort Roy, Sourav
collection PubMed
description Borrelial pathogens are vector-borne etiological agents of Lyme disease, relapsing fever, and Borrelia miyamotoi disease. These spirochetes each encode several surface-localized lipoproteins that bind to components of the human complement system. BBK32 is an example of a borrelial lipoprotein that protects the Lyme disease spirochete from complement-mediated attack. The complement inhibitory activity of BBK32 arises from an alpha helical C-terminal domain that interacts directly with the initiating protease of the classical pathway, C1r. Borrelia miyamotoi spirochetes encode BBK32 orthologs termed FbpA and FbpB, and these proteins also inhibit C1r, albeit via distinct recognition mechanisms. The C1r-inhibitory activities of a third ortholog termed FbpC, which is found exclusively in relapsing fever spirochetes, remains unknown. Here we report the crystal structure of the C-terminal domain of B. hermsii FbpC to a limiting resolution of 1.5 Å. Surface plasmon resonance studies and assays of complement function demonstrate that FbpC retains potent BBK32-like anti-complement activities. Based on the structure of FbpC, we hypothesized that conformational dynamics of the complement inhibitory domains of borrelial C1r inhibitors may differ. To test this, we utilized the crystal structures of the C-terminal domains of BBK32, FbpA, FbpB, and FbpC to carry out 1 µs molecular dynamics simulations, which revealed borrelial C1r inhibitors adopt energetically favored open and closed states defined by two functionally critical regions. This study advances our understanding of how protein dynamics contribute to the function of bacterial immune evasion proteins and reveals a surprising plasticity in the structures of borrelial C1r inhibitors.
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spelling pubmed-100027282023-03-11 “Conformational dynamics of C1r inhibitor proteins from Lyme disease and relapsing fever spirochetes” Roy, Sourav Booth, Charles E. Powell-Pierce, Alexandra D. Schulz, Anna M. Skare, Jon T. Garcia, Brandon L. bioRxiv Article Borrelial pathogens are vector-borne etiological agents of Lyme disease, relapsing fever, and Borrelia miyamotoi disease. These spirochetes each encode several surface-localized lipoproteins that bind to components of the human complement system. BBK32 is an example of a borrelial lipoprotein that protects the Lyme disease spirochete from complement-mediated attack. The complement inhibitory activity of BBK32 arises from an alpha helical C-terminal domain that interacts directly with the initiating protease of the classical pathway, C1r. Borrelia miyamotoi spirochetes encode BBK32 orthologs termed FbpA and FbpB, and these proteins also inhibit C1r, albeit via distinct recognition mechanisms. The C1r-inhibitory activities of a third ortholog termed FbpC, which is found exclusively in relapsing fever spirochetes, remains unknown. Here we report the crystal structure of the C-terminal domain of B. hermsii FbpC to a limiting resolution of 1.5 Å. Surface plasmon resonance studies and assays of complement function demonstrate that FbpC retains potent BBK32-like anti-complement activities. Based on the structure of FbpC, we hypothesized that conformational dynamics of the complement inhibitory domains of borrelial C1r inhibitors may differ. To test this, we utilized the crystal structures of the C-terminal domains of BBK32, FbpA, FbpB, and FbpC to carry out 1 µs molecular dynamics simulations, which revealed borrelial C1r inhibitors adopt energetically favored open and closed states defined by two functionally critical regions. This study advances our understanding of how protein dynamics contribute to the function of bacterial immune evasion proteins and reveals a surprising plasticity in the structures of borrelial C1r inhibitors. Cold Spring Harbor Laboratory 2023-03-01 /pmc/articles/PMC10002728/ /pubmed/36909632 http://dx.doi.org/10.1101/2023.03.01.530473 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Roy, Sourav
Booth, Charles E.
Powell-Pierce, Alexandra D.
Schulz, Anna M.
Skare, Jon T.
Garcia, Brandon L.
“Conformational dynamics of C1r inhibitor proteins from Lyme disease and relapsing fever spirochetes”
title “Conformational dynamics of C1r inhibitor proteins from Lyme disease and relapsing fever spirochetes”
title_full “Conformational dynamics of C1r inhibitor proteins from Lyme disease and relapsing fever spirochetes”
title_fullStr “Conformational dynamics of C1r inhibitor proteins from Lyme disease and relapsing fever spirochetes”
title_full_unstemmed “Conformational dynamics of C1r inhibitor proteins from Lyme disease and relapsing fever spirochetes”
title_short “Conformational dynamics of C1r inhibitor proteins from Lyme disease and relapsing fever spirochetes”
title_sort “conformational dynamics of c1r inhibitor proteins from lyme disease and relapsing fever spirochetes”
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10002728/
https://www.ncbi.nlm.nih.gov/pubmed/36909632
http://dx.doi.org/10.1101/2023.03.01.530473
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