Structural basis for recognition of receptor CSPG4 by Clostridium difficile toxin B
EMSL Project ID
50992
Abstract
Clostridium difficile (C. diff) is an opportunistic pathogen, which establishes in the colon when the gut microbiota is disrupted by antibiotics or diseases. C. difficile infection (CDI) leads to diarrhea and life-threatening pseudomembranous colitis, which are largely caused by two homologous virulence factors C. difficile toxin A (TcdA) and toxin B (TcdB), of which TcdB alone is capable of causing full spectrum of diseases. It is widely accepted that the toxins enter the cells through endocytosis by binding to cell surface receptors. Chondroitin sulfate proteoglycan 4 (CSPG4) and frizzled proteins (FZDs) are the two major TcdB receptors. We have recently determined the crystal structure of a TcdB fragment in complex with FZD2, which reveals a novel mechanism by which TcdB binds to FZDs for cell entry and simultaneously inhibits Wnt signaling. Here, we propose to determine the structure of TcdB holotoxin in complex with CSPG4 using CryoEM. This structure together with the TcdB-FZD complex will establish the molecular basis for toxin-receptor recognition, which will help to advance mechanistic understanding of the biology and pathogenesis of TcdB and therapy of CDI. Furthermore, CSPG4 is implicated in several signaling pathways that are believed to drive cancer progression, particularly proliferation, motility and metastatic spread. Therefore, the structure of TcdB-CSPG4 complex could be used as a blueprint to develop TcdB or its domains into pharmacological tools for cancer research and therapeutic applications.
Project Details
Start Date
2019-08-01
End Date
2020-01-14
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members