Actin: Structure, Function, Dynamics, and Interactions with Bacterial Toxins

Clostridial Neurotoxins: Structure, Function, and Implications to Other Bacterial Toxins

Microorganisms ◽

10.3390/microorganisms9112206 ◽

2021 ◽

Vol 9 (11) ◽

pp. 2206

Author(s):

Shuowei Cai ◽

Raj Kumar ◽

Bal Ram Singh

Keyword(s):

Structure Function ◽

Molten Globule ◽

Flexible Structures ◽

Bacterial Toxins ◽

Gram Positive ◽

Gram Positive Bacteria ◽

Clostridial Neurotoxins ◽

Structure Function Relationship ◽

Function Relationship ◽

Relationship Of

Gram-positive bacteria are ancient organisms. Many bacteria, including Gram-positive bacteria, produce toxins to manipulate the host, leading to various diseases. While the targets of Gram-positive bacterial toxins are diverse, many of those toxins use a similar mechanism to invade host cells and exert their functions. Clostridial neurotoxins produced by Clostridial tetani and Clostridial botulinum provide a classical example to illustrate the structure–function relationship of bacterial toxins. Here, we critically review the recent progress of the structure–function relationship of clostridial neurotoxins, including the diversity of the clostridial neurotoxins, the mode of actions, and the flexible structures required for the activation of toxins. The mechanism clostridial neurotoxins use for triggering their activity is shared with many other Gram-positive bacterial toxins, especially molten globule-type structures. This review also summarizes the implications of the molten globule-type flexible structures to other Gram-positive bacterial toxins. Understanding these highly dynamic flexible structures in solution and their role in the function of bacterial toxins not only fills in the missing link of the high-resolution structures from X-ray crystallography but also provides vital information for better designing antidotes against those toxins.

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Evolutionary Features in the Structure and Function of Bacterial Toxins

Toxins ◽

10.3390/toxins11010015 ◽

2019 ◽

Vol 11 (1) ◽

pp. 15 ◽

Cited By ~ 5

Author(s):

Raj Kumar ◽

Thomas M. Feltrup ◽

Roshan V. Kukreja ◽

Kruti B. Patel ◽

Shuowei Cai ◽

...

Keyword(s):

Structure Function ◽

Protein Dynamics ◽

Evolutionary Model ◽

Structure And Function ◽

Bacterial Toxins ◽

Dimensional Structure ◽

Careful Study ◽

Enzymatic Function ◽

Evolutionary Features ◽

And Function

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.

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