Structural Dynamics of Receptor Recognition and PH-induced Dissociation of Full-length Clostridioides Difficile Toxin B

Overview

Journal PLoS Biol

Specialty Biology

Date 2022 Mar 24

PMID 35324891

Authors

Mengqiu Jiang

Joonyoung Shin

Rudo Simeon

Jeng-Yih Chang

Ran Meng

Yuhang Wang

Omkar Shinde

Pingwei Li

Zhilei Chen

Junjie Zhang

Affiliations

Soon will be listed here.

Abstract

Clostridioides difficile secretes Toxin B (TcdB) as one of its major virulence factors, which binds to intestinal epithelial and subepithelial receptors, including frizzled proteins and chondroitin sulfate proteoglycan 4 (CSPG4). Here, we present cryo-EM structures of full-length TcdB in complex with the CSPG4 domain 1 fragment (D1401-560) at cytosolic pH and the cysteine-rich domain of frizzled-2 (CRD2) at both cytosolic and acidic pHs. CSPG4 specifically binds to the autoprocessing and delivery domains of TcdB via networks of salt bridges, hydrophobic and aromatic/proline interactions, which are disrupted upon acidification eventually leading to CSPG4 drastically dissociating from TcdB. In contrast, FZD2 moderately dissociates from TcdB under acidic pH, most likely due to its partial unfolding. These results reveal structural dynamics of TcdB during its preentry step upon endosomal acidification, which provide a basis for developing therapeutics against C. difficile infections.

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