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Conformational dynamics of complement protease C1r inhibitor proteins from Lyme disease– and relapsing fever–causing spirochetes
Borrelial pathogens are vector-borne etiological agents known to cause Lyme disease, relapsing fever, and Borrelia miyamotoi disease. These spirochetes each encode several surface-localized lipoproteins that bind components of the human complement system to evade host immunity. One borrelial lipopro...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413161/ https://www.ncbi.nlm.nih.gov/pubmed/37380082 http://dx.doi.org/10.1016/j.jbc.2023.104972 |
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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 known to cause Lyme disease, relapsing fever, and Borrelia miyamotoi disease. These spirochetes each encode several surface-localized lipoproteins that bind components of the human complement system to evade host immunity. One borrelial lipoprotein, BBK32, protects the Lyme disease spirochete from complement-mediated attack via an alpha helical C-terminal domain that interacts directly with the initiating protease of the classical complement pathway, C1r. In addition, the B. miyamotoi BBK32 orthologs FbpA and FbpB 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–causing spirochetes, remains unknown. Here, we report the crystal structure of the C-terminal domain of Borrelia hermsii FbpC to a limiting resolution of 1.5 Å. We used surface plasmon resonance and assays of complement function to demonstrate that FbpC retains potent BBK32-like anticomplement 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 molecular dynamics simulations, which revealed borrelial C1r inhibitors adopt energetically favored open and closed states defined by two functionally critical regions. Taken together, these results advance our understanding of how protein dynamics contribute to the function of bacterial immune evasion proteins and reveal a surprising plasticity in the structures of borrelial C1r inhibitors. |
format | Online Article Text |
id | pubmed-10413161 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-104131612023-08-11 Conformational dynamics of complement protease C1r inhibitor proteins from Lyme disease– and relapsing fever–causing spirochetes Roy, Sourav Booth, Charles E. Powell-Pierce, Alexandra D. Schulz, Anna M. Skare, Jon T. Garcia, Brandon L. J Biol Chem Research Article Borrelial pathogens are vector-borne etiological agents known to cause Lyme disease, relapsing fever, and Borrelia miyamotoi disease. These spirochetes each encode several surface-localized lipoproteins that bind components of the human complement system to evade host immunity. One borrelial lipoprotein, BBK32, protects the Lyme disease spirochete from complement-mediated attack via an alpha helical C-terminal domain that interacts directly with the initiating protease of the classical complement pathway, C1r. In addition, the B. miyamotoi BBK32 orthologs FbpA and FbpB 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–causing spirochetes, remains unknown. Here, we report the crystal structure of the C-terminal domain of Borrelia hermsii FbpC to a limiting resolution of 1.5 Å. We used surface plasmon resonance and assays of complement function to demonstrate that FbpC retains potent BBK32-like anticomplement 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 molecular dynamics simulations, which revealed borrelial C1r inhibitors adopt energetically favored open and closed states defined by two functionally critical regions. Taken together, these results advance our understanding of how protein dynamics contribute to the function of bacterial immune evasion proteins and reveal a surprising plasticity in the structures of borrelial C1r inhibitors. American Society for Biochemistry and Molecular Biology 2023-06-27 /pmc/articles/PMC10413161/ /pubmed/37380082 http://dx.doi.org/10.1016/j.jbc.2023.104972 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Roy, Sourav Booth, Charles E. Powell-Pierce, Alexandra D. Schulz, Anna M. Skare, Jon T. Garcia, Brandon L. Conformational dynamics of complement protease C1r inhibitor proteins from Lyme disease– and relapsing fever–causing spirochetes |
title | Conformational dynamics of complement protease C1r inhibitor proteins from Lyme disease– and relapsing fever–causing spirochetes |
title_full | Conformational dynamics of complement protease C1r inhibitor proteins from Lyme disease– and relapsing fever–causing spirochetes |
title_fullStr | Conformational dynamics of complement protease C1r inhibitor proteins from Lyme disease– and relapsing fever–causing spirochetes |
title_full_unstemmed | Conformational dynamics of complement protease C1r inhibitor proteins from Lyme disease– and relapsing fever–causing spirochetes |
title_short | Conformational dynamics of complement protease C1r inhibitor proteins from Lyme disease– and relapsing fever–causing spirochetes |
title_sort | conformational dynamics of complement protease c1r inhibitor proteins from lyme disease– and relapsing fever–causing spirochetes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413161/ https://www.ncbi.nlm.nih.gov/pubmed/37380082 http://dx.doi.org/10.1016/j.jbc.2023.104972 |
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