Sequence Diversity in the Pore-Forming Motifs of the Membrane-Damaging Protein Toxins
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Sequence Diversity in the Pore‑Forming Motifs of the Membrane‑Damaging Protein Toxins Anish Kumar Mondal1 · Pratima Verma1 · Kusum Lata1 · Mahendra Singh1 · Shamaita Chatterjee1 · Kausik Chattopadhyay1 Received: 11 July 2020 / Accepted: 8 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Pore-forming proteins/toxins (PFPs/PFTs) are the distinct class of membrane-damaging proteins. They act by forming oligomeric pores in the plasma membranes. PFTs and PFPs from diverse organisms share a common mechanism of action, in which the designated pore-forming motifs of the membrane-bound protein molecules insert into the membrane lipid bilayer to create the water-filled pores. One common characteristic of these pore-forming motifs is that they are amphipathic in nature. In general, the hydrophobic sidechains of the pore-forming motifs face toward the hydrophobic core of the membranes, while the hydrophilic residues create the lining of the water-filled pore lumen. Interestingly, pore-forming motifs of the distinct subclass of PFPs/PFTs share very little sequence similarity with each other. Therefore, the common guiding principle that governs the sequence-to-structure paradigm in the mechanism of action of these PFPs/PFTs still remains an enigma. In this article, we discuss this notion using the examples of diverse groups of membrane-damaging PFPs/PFTs. Graphic Abstract
Keywords Pore-forming toxin · Pore-forming protein · Membranes · Beta-PFT · Alpha-PFT
Introduction
* Kausik Chattopadhyay [email protected] 1
Centre for Protein Science, Design and Engineering, Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Sector 81, S. A. S. Nagar, Manauli, Mohali, Punjab 140306, India
Membrane pore-formation is one of the most efficient mechanisms of cell-killing employed by the diverse life forms. Such pathophysiological function is achieved by a unique group of protein toxins known as the pore-forming toxins (PFTs). PFTs form pores of specific size and stoichiometry in the lipid bilayer of the target cell membranes. This allows unrestricted movement of ions, water, and other molecules through the cell membranes, which in turn disrupts the cellular homeostasis leading to the cell-death (Bischofberger
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et al. 2012; Dal Peraro and van der Goot 2016; Mondal et al. 2018). PFTs are generally produced as soluble monomers. Upon encountering the target plasma membranes, they assemble into oligomeric complexes, which are finally converted into the transmembrane pores (Gonzalez et al. 2008). Presence of the PFTs is ubiquitously found in diverse organisms that include bacteria, fungi, sea anemones, plants, and even higher vertebrates such as humans. These proteins are produced for different purposes in different organisms. Pathogenic bacteria utilize PFTs as their virulence factors, whereas eukaryotic organisms usually use them for the defense mechanisms. Higher vertebrates produce poreforming proteins (PFPs) to kill
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