Work

Structure and conformational dynamics of Clostridioides difficile toxin A

Year: 2022

Type: article

Abstract: infection (CDI). Here, we report the 3.18-Å resolution crystal structure of a TcdA fragment (residues L843-T2481), which advances our understanding of the complete structure of TcdA holotoxin. Our structural analysis, together with complementary single molecule FRET and limited proteolysis studies, reveal that TcdA adopts a dynamic structure and its CROPs domain can sample a spectrum of open and closed conformations in a pH-dependent manner. Furthermore, a small globular subdomain (SGS) and the CROPs protect the pore-forming region of TcdA in the closed state at neutral pH, which could contribute to modulating the pH-dependent pore formation of TcdA. A rationally designed TcdA mutation that trapped the CROPs in the closed conformation showed drastically reduced cytotoxicity. Taken together, these studies shed new lights into the conformational dynamics of TcdA and its roles in TcdA intoxication.

Source: Life Science Alliance

DOI: 10.26508/lsa.202201383

Authors: Baohua Chen, Sujit Basak, Peng Chen, Changcheng Zhang, Kay Perry, Songhai Tian, Clinton Yu, Min Dong, Lan Huang, Mark E Bowen, Rongsheng Jin

Institutions: University of California, Irvine, Stony Brook University, Argonne National Laboratory, Cornell University, Boston Children's Hospital, Harvard University

Language: English

Topic: Clostridium difficile and Clostridium perfringens research

Subfield: Infectious Diseases

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,500

Funders: U.S. Department of Energy, Burroughs Wellcome Fund, Office of Science, National Institute of Mental Health, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Argonne National Laboratory

Awards: G102163711, G107546177, G1313983767, G1505794299, G1664757510, G1783298418, G2101401529, G2287611682, Single Molecule Analysis of MAGUK Structure and Ligand Binding, G262962599, G2887060908, G3075337988, G340565428, G409777406, G4155925329, G4429385918, G4783937286, Structural basis for recognition of SV2 by type E botulinum neurotoxin, G498139845, G5106849484, Molecular mechanisms of botulinum neurotoxin neutralization, G6848031779, Structure and Function of C. Difficile Toxins, G6918803902, G7154682661, G7368700025, Structural dynamics and function of the COP9 signalosome, G78868261, Molecular basis of action and pathogenesis of Clostridium difficile toxin B, Proteomics of the Proteasome Interacting Networks, G847065681, Structural basis of Rho glucosylation by Clostridium difficile toxins, Resolving the intoxication mechanism of botulinum neurotoxins using single molecule structural biology, NE-CAT: A Resource for Advanced Macromolecular Crystallography, Developing broad-spectrum therapeutics against C. difficile toxins, G969889393, G993149817

OpenAlex ID: W4221039124

FWCI: 1.946

Cites: 52

Cited by: 17

Related to: 10