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Bacterial Toxins: Structure–Function Relationship

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A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (30 November 2018) | Viewed by 44028

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Special Issue Editor

Dr. Subramanyam Swaminathan

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Guest Editor

Biology Department, Brookhaven National Laboratory, Upton, NY 11973, USA
Interests: bacterial toxins; botulinum neurotoxins; macromolecular complexes; protein crystallography; structure–function relationship; drug discovery; protein–protein interactions

Special Issue Information

Dear Colleagues:

Bacterial toxins are classified into two major types: Endotoxins and exotoxins. Endotoxins are specifically referred to as cell-associated toxins—non-protein lipopolysaccharides associated with the cell wall of Gram negative bacteria. They act at, or near, the bacterial growth site. Exotoxins are proteins secreted by bacteria and act at a site farther away from the secretion site. Enterotoxins, neurotoxins, cytotoxins, lysins (e.g., hemolysin), gangrene-producing toxins, etc., are some examples of bacterial endotoxins, the names also indicating the site of action of the toxin. Most of the exotoxins have enzymatic activity. Many bacterial toxins consist of two components, A and B subunits, and are called AB toxins. Subunit B is involved in binding to the target, a specific receptor and subunit A performs the catalytic action on a substrate. Diphtheria toxin and botulinum toxins are AB toxins which contain a translocation component in the binding subunit. Shiga and Cholera toxins are AB5 toxins indicating the presence of five binding subunits and one A subunit. Pore-forming toxins (PFT) form pores in the membrane for translocation of toxin component as in anthrax toxin and colicin or involved in ion movement disruption as in toxins. Interestingly, some toxins, such as botulinum toxins, have clinical applications.

This Special Issue will focus on exotoxins, their structures and biological function explained on the basis of their structure, the major emphasis being on structure– function relationships and counter measures to block the toxin activity. The structures of stand-alone individual protein toxins provide basic information about the fold and organization of the different components. However, their complexes with appropriate substrates and/or receptors are important since they help in both understanding the protein–protein interaction responsible for toxic activity and ways to disrupt the interaction to mitigate the effect of toxin. Recent developments in cryo-electron microscopy have made it possible to study large multi-protein complexes at near atomic resolution. This Special Issue will cover the expansive structural information available so far.

Dr. Subramanyam Swaminathan
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a double-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Toxins is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

bacterial toxins
three-dimensional structure
structure-function
toxin-receptor/substrate complexes
counter measures

Published Papers (6 papers)

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Research

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16 pages, 31537 KiB

Open AccessFeature PaperArticle

Crystal Structure of Botulinum Neurotoxin A2 in Complex with the Human Protein Receptor SV2C Reveals Plasticity in Receptor Binding

by Robert Gustafsson, Sicai Zhang, Geoffrey Masuyer, Min Dong and Pål Stenmark

Toxins 2018, 10(4), 153; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10040153 - 12 Apr 2018

Cited by 14 | Viewed by 7459

Abstract

Botulinum neurotoxins (BoNTs) are a family of highly dangerous bacterial toxins, with seven major serotypes (BoNT/A-G). Members of BoNTs, BoNT/A1 and BoNT/B1, have been utilized to treat an increasing number of medical conditions. The clinical trials are ongoing for BoNT/A2, another subtype of BoNT/A, which showed promising therapeutic properties. Both BoNT/A1 and BoNT/A2 utilize three isoforms of synaptic vesicle protein SV2 (SV2A, B, and C) as their protein receptors. We here present a high resolution (2.0 Å) co-crystal structure of the BoNT/A2 receptor-binding domain in complex with the human SV2C luminal domain. The structure is similar to previously reported BoNT/A-SV2C complexes, but a shift of the receptor-binding segment in BoNT/A2 rotates SV2C in two dimensions giving insight into the dynamic behavior of the interaction. Small differences in key residues at the binding interface may influence the binding to different SV2 isoforms, which may contribute to the differences between BoNT/A1 and BoNT/A2 observed in the clinic. Full article

(This article belongs to the Special Issue Bacterial Toxins: Structure–Function Relationship)

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11 pages, 2776 KiB

Open AccessArticle

The Replacement of five Consecutive Amino Acids in the Cyt1A Protein of Bacillus thuringiensis Enhances its Cytotoxic Activity against Lung Epithelial Cancer Cells

by Kavita Nair, Ahmad Iskandarani, Roda Al-Thani, Ramzi Mohammad and Samir Jaoua

Toxins 2018, 10(3), 125; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10030125 - 16 Mar 2018

Cited by 3 | Viewed by 4198

Abstract

Cyt1A protein is a cytolytic protein encoded by the cyt gene of Bacillus thuringiensis subsp. israelensis (Bti) as part of the parasporal crystal proteins produced during the sporulation. Cyt1A protein is unique compared to the other endotoxins present in these parasporal crystals. Unlike δ-endotoxins, Cyt1A protein does not require receptors to bind to the target cell and activate the toxicity. It has the ability to affect a broad range of cell types and organisms, due to this characteristic. Cyt1A has been recognized to not only target the insect cells directly, but also recruit other endotoxins by acting as receptors. Due to these mode of actions, Cyt1A has been studied for its cytolytic activity against human cancer cell lines, although not extensively. In this study, we report a novel Cyt1A protein produced by a Bti strain QBT229 isolated from Qatar. When tested for its cytotoxicity against lung cancer cells, this local strain showed considerably higher activity compared to that of the reference Bti and other strains tested. The possible reasons for such enhanced activity were explored at the gene and protein levels. It was evidenced that five consecutive amino acid replacements in the β8 sheet of the Cyt1A protein enhanced the cytotoxicity against the lung epithelial cancer cells. Such novel Cyt1A protein with high cytotoxicity against lung cancer cells has been characterized and reported through this study. Full article

(This article belongs to the Special Issue Bacterial Toxins: Structure–Function Relationship)

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Review

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23 pages, 1843 KiB

Open AccessReview

Evolutionary Features in the Structure and Function of Bacterial Toxins

by Raj Kumar, Thomas M. Feltrup, Roshan V. Kukreja, Kruti B. Patel, Shuowei Cai and Bal Ram Singh

Toxins 2019, 11(1), 15; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11010015 - 03 Jan 2019

Cited by 17 | Viewed by 6400

Abstract

Toxins can function both as a harmful and therapeutic molecule, depending on their concentrations. The diversity in their function allows us to ask some very pertinent questions related to their origin and roles: (a) What makes them such effective molecules? (b) Are there evolutionary features encoded within the structures of the toxins for their function? (c) Is structural hierarchy in the toxins important for maintaining their structure and function? (d) Do protein dynamics play a role in the function of toxins? and (e) Do the evolutionary connections to these unique features and functions provide the fundamental points in driving evolution? In light of the growing evidence in structural biology, it would be appropriate to suggest that protein dynamics and flexibility play a much bigger role in the function of the toxin than the structure itself. Discovery of IDPs (intrinsically disorder proteins), multifunctionality, and the concept of native aggregation are shaking the paradigm of the requirement of a fixed three-dimensional structure for the protein’s function. Growing evidence supporting the above concepts allow us to redesign the structure-function aspects of the protein molecules. An evolutionary model is necessary and needs to be developed to study these important aspects. The criteria for a well-defined model would be: (a) diversity in structure and function, (b) unique functionality, and (c) must belong to a family to define the evolutionary relationships. All these characteristics are largely fulfilled by bacterial toxins. Bacterial toxins are diverse and widely distributed in all three forms of life (Bacteria, Archaea and Eukaryotes). Some of the unique characteristics include structural folding, sequence and functional combination of domains, targeting a cellular process to execute their function, and most importantly their flexibility and dynamics. In this work, we summarize certain unique aspects of bacterial toxins, including role of structure in defining toxin function, uniqueness in their enzymatic function, and interaction with their substrates and other proteins. Finally, we have discussed the evolutionary aspects of toxins in detail, which will help us rethink the current evolutionary theories. A careful study, and appropriate interpretations, will provide answers to several questions related to the structure-function relationship of proteins, in general. Additionally, this will also allow us to refine the current evolution theories. Full article

(This article belongs to the Special Issue Bacterial Toxins: Structure–Function Relationship)

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16 pages, 3342 KiB

Open AccessReview

The Modes of Action of MARTX Toxin Effector Domains

by Byoung Sik Kim

Toxins 2018, 10(12), 507; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10120507 - 02 Dec 2018

Cited by 20 | Viewed by 5273

Abstract

Many Gram-negative bacterial pathogens directly deliver numerous effector proteins from the bacterium to the host cell, thereby altering the target cell physiology. The already well-characterized effector delivery systems are type III, type IV, and type VI secretion systems. Multifunctional autoprocessing repeats-in-toxin (MARTX) toxins are another effector delivery platform employed by some genera of Gram-negative bacteria. These single polypeptide exotoxins possess up to five effector domains in a modular fashion in their central regions. Upon binding to the host cell plasma membrane, MARTX toxins form a pore using amino- and carboxyl-terminal repeat-containing arms and translocate the effector domains into the cells. Consequently, MARTX toxins affect the integrity of the host cells and often induce cell death. Thus, they have been characterized as crucial virulence factors of certain human pathogens. This review covers how each of the MARTX toxin effector domains exhibits cytopathic and/or cytotoxic activities in cells, with their structural features revealed recently. In addition, future directions for the comprehensive understanding of MARTX toxin-mediated pathogenesis are discussed. Full article

(This article belongs to the Special Issue Bacterial Toxins: Structure–Function Relationship)

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18 pages, 3925 KiB

Open AccessReview

Variations in the Botulinum Neurotoxin Binding Domain and the Potential for Novel Therapeutics

by Jonathan R. Davies, Sai Man Liu and K. Ravi Acharya

Toxins 2018, 10(10), 421; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10100421 - 20 Oct 2018

Cited by 22 | Viewed by 7468

Abstract

Botulinum neurotoxins (BoNTs) are categorised into immunologically distinct serotypes BoNT/A to /G). Each serotype can also be further divided into subtypes based on differences in amino acid sequence. BoNTs are ~150 kDa proteins comprised of three major functional domains: an N-terminal zinc metalloprotease light chain (LC), a translocation domain (H_N), and a binding domain (H_C). The H_C is responsible for targeting the BoNT to the neuronal cell membrane, and each serotype has evolved to bind via different mechanisms to different target receptors. Most structural characterisations to date have focussed on the first identified subtype within each serotype (e.g., BoNT/A1). Subtype differences within BoNT serotypes can affect intoxication, displaying different botulism symptoms in vivo, and less emphasis has been placed on investigating these variants. This review outlines the receptors for each BoNT serotype and describes the basis for the highly specific targeting of neuronal cell membranes. Understanding receptor binding is of vital importance, not only for the generation of novel therapeutics but also for understanding how best to protect from intoxication. Full article

(This article belongs to the Special Issue Bacterial Toxins: Structure–Function Relationship)

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9 pages, 5929 KiB

Open AccessReview

Structural and Mechanistic Features of ClyA-Like α-Pore-Forming Toxins

by Bastian Bräuning and Michael Groll

Toxins 2018, 10(9), 343; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins10090343 - 23 Aug 2018

Cited by 9 | Viewed by 4207

Abstract

Recent technological advances have seen increasing numbers of complex structures from diverse pore-forming toxins (PFT). The ClyA family of α-PFTs comprises a broad variety of assemblies including single-, two- and three-component toxin systems. With crystal structures available for soluble subunits of all major groups in this extended protein family, efforts now focus on obtaining molecular insights into physiological pore formation. This review provides an up-to-date discussion on common and divergent structural and functional traits that distinguish the various ClyA family PFTs. Open questions of this research topic are outlined and discussed. Full article

(This article belongs to the Special Issue Bacterial Toxins: Structure–Function Relationship)

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