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Structural Elucidation of the Clostridioides Difficile Transferase Toxin Reveals a Single-Site Binding Mode for the Enzyme

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Structural Elucidation of the Clostridioides Difficile Transferase Toxin Reveals a Single-Site Binding Mode for the Enzyme Structural elucidation of the Clostridioides difficile transferase toxin reveals a single-site binding mode for the enzyme Michael J. Sheedloa,b, David M. Andersona,b, Audrey K. Thomasa, and D. Borden Lacya,b,1 aDepartment of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; and bThe Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN 37232 Edited by Stephen C. Harrison, Boston Children’s Hospital, Boston, MA, and approved February 5, 2020 (received for review November 21, 2019) Clostridioides difficile is a Gram-positive, pathogenic bacterium described a synergistic effect between CDT and TcdA/B which and a prominent cause of hospital-acquired diarrhea in the United enhanced innate immune signaling and dampened the eosinophil States. The symptoms of C. difficile infection are caused by the response (15). Although these two mechanisms are seemingly activity of three large toxins known as toxin A (TcdA), toxin B unrelated, it is possible that the presence of CDT is not restricted (TcdB), and the C. difficile transferase toxin (CDT). Reported here to either of these functions and that the combination of these is a 3.8-Å cryo–electron microscopy (cryo-EM) structure of CDT, a two events leads to increased disease severity during infection. bipartite toxin comprised of the proteins CDTa and CDTb. We The structure of each component of CDT has been previously observe a single molecule of CDTa bound to a CDTb heptamer. determined. CDTa has been characterized by X-ray crystallog- The formation of the CDT complex relies on the interaction of an raphy and is known to consist of two domains: a pseudo-ADP N-terminal adaptor and pseudoenzyme domain of CDTa with six ribosyltransferase (pADPRT) domain and an ADP ribosyltransferase subunits of the CDTb heptamer. CDTb is observed in a preinsertion (ADPRT) domain. The ADPRT domain is the enzymatic com- state, a conformation observed in the transition of prepore to ponent of CDT and functions by modifying actin, leading to a β -barrel pore, although we also observe a single bound CDTa in distinct cytopathic cell-rounding phenotype (Fig. 1A) (16). The β the prepore and -barrel conformations of CDTb. The binding pADPRT and ADPRT domains are similar in sequence and interaction appears to prime CDTa for translocation as the adaptor structure, and both are conserved among members of the Iota MICROBIOLOGY subdomain enters the lumen of the preinsertion state channel. family of binary toxins, as well as the related C2 toxin produced These structural observations advance the understanding of how by Clostridium botulinum (SI Appendix, Fig. S1 A and B). Because a single protein, CDTb, can mediate the delivery of a large enzyme, these two domains are so similar it has been hypothesized that CDTa, into the cytosol of mammalian cells. the structure of CDTa arose from an ancestral gene duplication event, although the benefit of conserving this architecture binary toxin | cryo-EM | Iota toxin | Clostridium throughout evolution remains unclear (7, 12). The pore-forming component of CDT is CDTb, a five-domain protein that forms C lostridioides difficile is a pathogenic, Gram-positive bacte- oligomeric pores to facilitate the transfer of CDTa into the host rium that forms a hardy spore, which can persist through cytoplasm. The five domains of CDTb are called D1–D3, D3′,and extreme conditions and can be difficult to eradicate (1). The spores are present in the environment and are able to infect Significance humans via the fecal–oral route. In situations where the gut microbiota has been disrupted, most frequently through the use Clostridioides difficile Clostridium difficile of broad-spectrum antibiotics, C. difficile can colonize and pro- (formerly ) is the lead- liferate in the colon to cause disease. C. difficile infection (CDI) ing cause of hospital-acquired diarrhea in the United States. The C. difficile has become the leading cause of hospital-acquired diarrhea in pathology resulting from infection has been attributed the United States and leads to billions of dollars in additional to the activity of up to three secreted toxins known as toxin A C. difficile healthcare expenditures each year (2). The disease state is me- (TcdA), toxin B (TcdB), and the transferase toxin (CDT). diated by two large, homologous toxins termed toxin A (TcdA) Reported here is the near-atomic resolution structure of CDT, a and toxin B (TcdB) (3). Both TcdA and TcdB belong to the large bipartite toxin that is made up of two components called CDTa glucosylating family of toxins and function by modifying small Rho and CDTb. Our structure highlights a unique mode of toxin as- family GTPases, leading to cytoskeletal disruption and cell death sembly that is distinct from the previously characterized anthrax (4–6). Although these two toxins can alone elicit all known toxin. The orientation we observe appears to prime CDT for symptoms associated with CDI, some of the most problematic delivery into the host by placing the N-terminal domain of CDTa clinical strains also produce a third toxin termed the C. difficile at the entrance to the pore. transferase toxin (CDT, or binary toxin) (7–9). – Author contributions: M.J.S., D.M.A., and D.B.L. designed research; M.J.S., D.M.A., and CDT is an A B-type toxin and a member of the Iota family of A.K.T. performed research; M.J.S. and D.M.A. contributed new reagents/analytic tools; binary toxins. It is comprised of two polypeptide chains termed M.J.S., D.M.A., and D.B.L. analyzed data; and M.J.S., D.M.A., A.K.T., and D.B.L. wrote CDTa, which is the enzymatic component, and CDTb, which the paper. functions as the cell-binding, pore-forming, and delivery appa- The authors declare no competing interest. ratus (10–12). It is currently unclear what role CDT plays during This article is a PNAS Direct Submission. C. difficile pathogenesis, although the prevalence of it in the so- Published under the PNAS license. “ ” called hypervirulent strains suggests that it may be involved in Data deposition: The data described in this publication are made available through the promoting severe infection (9, 13). An initial study on this topic Electron Microscopy Data Bank (EMDB accession code 21016) and the Protein Data Bank noted the formation of microtubule protrusions from colonic (PDB accession code 6V1S). epithelial cells intoxicated by CDT (14). These protrusions are 1To whom correspondence may be addressed. Email: [email protected]. thought to be a direct result of actin depolymerization and have This article contains supporting information online at https://www.pnas.org/lookup/suppl/ been shown to interact with C. difficile, potentially allowing the doi:10.1073/pnas.1920555117/-/DCSupplemental. bacterium to persist at the site of infection. A second study First published March 2, 2020. www.pnas.org/cgi/doi/10.1073/pnas.1920555117 PNAS | March 17, 2020 | vol. 117 | no. 11 | 6139–6144 Downloaded by guest on September 27, 2021 Fig. 1. Structure of the Clostridioides difficile transferase toxin, or CDT. (A) CDT is a bipartite toxin that is comprised of two polypeptide chains termed CDTa and CDTb. CDTa consists of two domains called the pseudo-ADP ribosyltransferase domain (pADPRT, orange) and the ADP ribosyltransferase domain (ADPRT, red). Encoded within the N terminus of each domain is an adaptor (termed either A1 or A2 and shown in yellow and pink, respectively). CDTb consists of five domains termed D1–D3, D3′ and D4. (B) In our map of the CDT toxin, we have resolved one molecule of CDTa and one CDTb heptamer, colored as in A. On the left is the full map, and on the right is a split view showing the positioning of CDTa within the heptamer. (C) CDTa is centered on top of the CDTb heptamer and makes contact with six out of the seven chains of CDT. (CDTa is represented as a density map and is shown in the same color scheme as indicated in A, and CDTb is shown as a cartoon; chains are denoted A–G.) Protomers that are involved in mediating this interaction are highlighted in red. (D) The structure of the N-terminal adaptor with the helices numbered as shown. (E) The N-terminal helix of CDTa, α1, is buried within the interior of the CDTb heptamer and ∼25 Å above the φ-clamp (shown in green, F). D4 (Fig. 1A) (17). These domains are responsible for preventing (Fig. 1B). When modeling this interaction, we were able to build premature oligomerization (D1), forming the oligomerization in- almost all of CDTa, although the resolution is markedly lower terface and β-barrel pore (D2/D3), interacting with glycans (D3′), within the ADPRT domain (SI Appendix,Fig.S4A). CDTb was and binding to the host cell receptor (D4). In addition to con- modeled as its first three domains: D1, D2, and D3 (residues 213– taining the pore-forming structure, the D2 domain contains an 556). Although D3′, D4, and the LSR receptor ectodomain were important regulatory feature known as the φ-clamp. This structure present within this sample, they were not observed in the map and consists of seven phenylalanines positioned in a ring at the en- thus could not be modeled. We observed and modeled two cal- trance to the pore and was first characterized in the context of the cium ions into D1, similar to those which were observed in PA related protein, anthrax toxin protective antigen (PA) (18). The (23). These calcium ions are present in all seven chains of the φ-clamp is needed to support cargo translocation and has been CDTb heptamer and are coordinated by a mixture of aspartic acid/ shown to be important for CDT function (17, 18).
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