Structural basis for selective modification of Rho and Ras GTPases by Clostridioides difficile toxin B

Liu, Zheng; Zhang, Sicai; Chen, Peng; Tian, Songhai; Zeng, Ji; Perry, Kay; Dong, Min; Jin, Rongsheng

doi:10.1126/sciadv.abi4582

Structural basis for selective modification of Rho and Ras GTPases by Clostridioides difficile toxin B

Journal Article · Fri Oct 22 00:00:00 EDT 2021 · Science Advances

DOI:https://doi.org/10.1126/sciadv.abi4582· OSTI ID:1831265

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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)

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.

View Accepted Manuscript (DOE)

Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1831265

Alternate ID(s):: OSTI ID: 1828055
OSTI ID: 1841204

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 43 Vol. 7; ISSN 2375-2548

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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