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The adenylate cyclase toxin RTX domain follows a series templated folding mechanism with implications for toxin activity
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SYSNO ASEP 0575651 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title The adenylate cyclase toxin RTX domain follows a series templated folding mechanism with implications for toxin activity Author(s) Chen, G. (CA)
Wang, H. (CA)
Bumba, Ladislav (MBU-M) RID, ORCID
Mašín, Jiří (MBU-M) RID, ORCID
Šebo, Peter (MBU-M) RID, ORCID
Li, H. (CA)Article number 105150 Source Title Journal of Biological Chemistry. - : Elsevier - ISSN 0021-9258
Roč. 299, č. 9 (2023)Number of pages 14 s. Language eng - English Country NL - Netherlands Keywords adenylate cyclase ; bacterial toxin ; optical tweezers ; protein folding ; single-molecule biophysics Subject RIV EE - Microbiology, Virology OECD category Microbiology R&D Projects GA22-01558S GA ČR - Czech Science Foundation (CSF) LX22NPO5103 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2023053 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_046/0015974 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Research Infrastructure CIISB III - 90242 - Masarykova univerzita / Středoevropský technologický institut Method of publishing Open access Institutional support MBU-M - RVO:61388971 UT WOS 001166519400001 EID SCOPUS 85170649644 DOI 10.1016/j.jbc.2023.105150 Annotation Folding of the Repeats-in-toxin (RTX) domain of the bacterial adenylate cyclase toxin-hemolysin (CyaA) is critical to its toxin activities and the virulence of the whooping cough agent Bordetella pertussis. The RTX domain (RD) contains five RTX blocks (RTX-i to RTX-v) and their folding is driven by the binding of calcium. However, the detailed molecular mechanism via which the folding signal transmits within the five RTX blocks remains unknown. By combining single molecule optical tweezers, protein engineering, and toxin activity assays, here we demonstrate that the folding of the RD follows a strict hierarchy, with the folding starting from its C-terminal block RTX-v and proceeding towards the N-terminal RTX-i block sequentially. Our results reveal a strict series, templated folding mechanism, where the folding signal is transmitted along the RD in a series fashion from its C terminus continuously to the N terminus. Due to the series nature of this folding signal transmission pathway, the folding of RD can be disrupted at any given RTX block, rendering the RTX blocks located N-terminally to the disruption site and the acylation region of CyaA unfolded and abolishing CyaA's toxin activities. Our results reveal key mechanistic insights into the secretion and folding process of CyaA and may open up new potential avenues towards designing new therapeutics to abolish toxin activity of CyaA and combat B. pertussis. Workplace Institute of Microbiology Contact Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Year of Publishing 2024 Electronic address https://www.sciencedirect.com/science/article/pii/S0021925823021786?via%3Dihub
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