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

Author:

Chiu Yu-Chuan,Yeh Min-Chi,Wang Chun-Hsiung,Chen Yu-An,Chang HsiangORCID,Lin Han-You,Ho Meng-ChiaoORCID,Lin Shih-MingORCID

Abstract

AbstractVibrio 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.

Funder

Ministry of Science and Technology, Taiwan

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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