Membrane binding and pore formation is Ca 2+ -dependent for the Clostridioides difficile binary toxin
Year: 2023
Type: preprint
Abstract: The C. difficile binary toxin (CDT) enters host cells via endosomal delivery like many other ‘AB’-type binary toxins. In this study, the cell-binding component of CDT, termed CDTb, was found to bind and form pores in lipid bilayers upon depleting free Ca 2+ ion concentrations, and not by lowering pH, as found for other binary toxins (i.e., anthrax). Cryoelectron microscopy, nuclear magnetic resonance spectroscopy, surface plasmon resonance, electrochemical impedance spectroscopy, CDT toxicity studies, and site directed mutagenesis show that dissociation of Ca 2+ from a single site in receptor binding domain 1 (RBD1) of CDTb is consistent with a molecular mechanism in which Ca 2+ dissociation from RBD1 induces a “trigger” via conformational exchange that enables CDTb to bind and form pores in endosomal membrane bilayers as free Ca 2+ concentrations decrease during CDT endosomal delivery. One-Sentence Summary Ca 2+ dissociation and unfolding of a receptor binding domain in CDTb activates pore-formation by the C. difficile binary toxin.
Institutions: University of Maryland, Baltimore, Institute for Bioscience and Biotechnology Research, Merck & Co., Inc., Rahway, NJ, USA (United States), National Institute of Standards and Technology, The Graduate Center, CUNY, City College of New York, City University of New York, CUNY Advanced Science Research Center
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4386001643