Structural basis for calcium-stimulating pore formation of Vibrio α-hemolysin

Yu-Chuan Chiu, Min-Chi Yeh, Chun-Hsiung Wang, Yu-An Chen, Hsiang Chang, Han-You Lin, Meng-Chiao Ho and Shih-Ming Lin ()
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Yu-Chuan Chiu: National Cheng Kung University
Min-Chi Yeh: Academia Sinica
Chun-Hsiung Wang: Academia Sinica
Yu-An Chen: National Cheng Kung University
Hsiang Chang: National Cheng Kung University
Han-You Lin: National Taiwan University
Meng-Chiao Ho: Academia Sinica
Shih-Ming Lin: National Cheng Kung University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Vibrio α-hemolysins (αHLs) are β-pore-forming toxins secreted by Vibrio pathogens, crucial for the facilitation of bacterial infections through host cell lysis. These toxins are produced as inactive precursors, requiring proteolytic maturation and membrane association for activation within host tissues. Here, we investigate Vibrio campbellii αHL (VcαHL), and establish that its hemolytic activity is significantly stimulated by calcium ions, with an EC50 that aligns with physiological calcium concentrations. Furthermore, we illustrate the vital contribution of calcium ions to the oligomerization of VcαHL on membranes. Using X-ray crystallography and cryo-electron microscopy, we decipher both the immature and assembled structures of VcαHL and elucidate the conformational changes corresponding to toxin assembly. We also identify a calcium-binding module that is integral for VcαHL’s calcium-dependent activation. These findings provide insights into the regulatory mechanisms of VcαHL and have the potential to inform the development of targeted therapeutic strategies against Vibrio infections.

Date: 2023
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DOI: 10.1038/s41467-023-41579-x

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