Structural basis for selective modification of Rho and Ras GTPases by Clostridioides difficile toxin B
Abstract
Toxin B (TcdB) is a primary cause of Clostridioides difficile infection (CDI). This toxin acts by glucosylating small GTPases in the Rho/Ras families, but the structural basis for TcdB recognition and selectivity of specific GTPase substrates remain unsolved. Here, we report the cocrystal structures of the glucosyltransferase domain (GTD) of two distinct TcdB variants in complex with human Cdc42 and R-Ras, respectively. These structures reveal a common structural mechanism by which TcdB recognizes Rho and R-Ras. Furthermore, we find selective clustering of adaptive residue changes in GTDs that determine their substrate preferences, which helps partition all known TcdB variants into two groups that display distinct specificities toward Rho or R-Ras. Mutations that selectively disrupt GTPases binding reduce the glucosyltransferase activity of the GTD and the toxicity of TcdB holotoxin. These findings establish the structural basis for TcdB recognition of small GTPases and reveal strategies for therapeutic interventions for CDI.
- Authors:
-
[1];
[2];
[1];
[2];
[2];
[3];
[2];
[1]
- Univ. of California, Irvine, CA (United States)
- Harvard Medical School, Boston, MA (United States). Boston Children's Hospital
- Cornell Univ., Ithaca, NY (United States); Argonne National Lab. (ANL), Lemont, IL (United States)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institutes of Health (NIH)
- OSTI Identifier:
- 1831265
- Grant/Contract Number:
- AC02-06CH11357; R01AI125704; R21AI139690; R21AI123920; R01NS080833; R01AI132387; R01AI139087; R21 CA235533; P30 GM124165; S10OD021527
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Science Advances
- Additional Journal Information:
- Journal Volume: 7; Journal Issue: 43; Journal ID: ISSN 2375-2548
- Publisher:
- AAAS
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Liu, Zheng, Zhang, Sicai, Chen, Peng, Tian, Songhai, Zeng, Ji, Perry, Kay, Dong, Min, and Jin, Rongsheng. Structural basis for selective modification of Rho and Ras GTPases by Clostridioides difficile toxin B. United States: N. p., 2021.
Web. doi:10.1126/sciadv.abi4582.
Liu, Zheng, Zhang, Sicai, Chen, Peng, Tian, Songhai, Zeng, Ji, Perry, Kay, Dong, Min, & Jin, Rongsheng. Structural basis for selective modification of Rho and Ras GTPases by Clostridioides difficile toxin B. United States. https://doi.org/10.1126/sciadv.abi4582
Liu, Zheng, Zhang, Sicai, Chen, Peng, Tian, Songhai, Zeng, Ji, Perry, Kay, Dong, Min, and Jin, Rongsheng. Fri .
"Structural basis for selective modification of Rho and Ras GTPases by Clostridioides difficile toxin B". United States. https://doi.org/10.1126/sciadv.abi4582. https://www.osti.gov/servlets/purl/1831265.
@article{osti_1831265,
title = {Structural basis for selective modification of Rho and Ras GTPases by Clostridioides difficile toxin B},
author = {Liu, Zheng and Zhang, Sicai and Chen, Peng and Tian, Songhai and Zeng, Ji and Perry, Kay and Dong, Min and Jin, Rongsheng},
abstractNote = {Toxin B (TcdB) is a primary cause of Clostridioides difficile infection (CDI). This toxin acts by glucosylating small GTPases in the Rho/Ras families, but the structural basis for TcdB recognition and selectivity of specific GTPase substrates remain unsolved. Here, we report the cocrystal structures of the glucosyltransferase domain (GTD) of two distinct TcdB variants in complex with human Cdc42 and R-Ras, respectively. These structures reveal a common structural mechanism by which TcdB recognizes Rho and R-Ras. Furthermore, we find selective clustering of adaptive residue changes in GTDs that determine their substrate preferences, which helps partition all known TcdB variants into two groups that display distinct specificities toward Rho or R-Ras. Mutations that selectively disrupt GTPases binding reduce the glucosyltransferase activity of the GTD and the toxicity of TcdB holotoxin. These findings establish the structural basis for TcdB recognition of small GTPases and reveal strategies for therapeutic interventions for CDI.},
doi = {10.1126/sciadv.abi4582},
journal = {Science Advances},
number = 43,
volume = 7,
place = {United States},
year = {Fri Oct 22 00:00:00 EDT 2021},
month = {Fri Oct 22 00:00:00 EDT 2021}
}
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