Relevance of Intrinsic Disorder in Protein Structure and Function

Feltrup, Thomas M.; Kumar, Raj; Singh, Bal Ram

doi:10.1007/978-3-319-43540-4_3

Cited by 3 publications

(3 citation statements)

References 118 publications

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“…This time frame allows us to confidently observe reaction half-lives (t 1/2 ) from 10-30 minutes, which is the expected range for Cys-reactive warheads. [61][62][63] Fitting fluorescent data obtained in kinetics mode to either Equations 1 or 2, constraining total enzyme ([E] T ), inhibitor concentration ([I]), substrate concentration ([S]), and substrate K M to defined values, yield values for k inact and K i . To validate these models, comparison of k inact and K i values obtained from this method and previously described assay methods is reported, vide infra.…”

Section: A Continuous Assay For Covalent Inhibitionmentioning

confidence: 99%

Catch and Anchor Approach To Combat Both Toxicity and Longevity of Botulinum Toxin A

Lin¹,

Olson²,

Sugane³

et al. 2020

J. Med. Chem.

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Section: A Continuous Assay For Covalent Inhibitionmentioning

confidence: 99%

Catch and Anchor Approach To Combat Both Toxicity and Longevity of Botulinum Toxin A

Lin¹,

Olson²,

Sugane³

et al. 2020

J. Med. Chem.

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“…Proposed hypotheses for BoNT (Botulinum Neurotoxin) survival include Tyr-phosphorylation [45], increased resistance to ubiquitination [46,47], palmitoylation of cysteine residues [48], and S-nitrosylation [48]. One possible explanation would be that each of these pathways is affected by the varying degree of flexibility of the LCs and the longevity differences between serotypes may be due to the effect on these pathways in which the structural parameters play an important role [49].…”

Section: Toxin Structures and Their Role In Defining Macromoleculamentioning

confidence: 99%

“…With many diseases being caused by disordered proteins in humans [26,35,50,51,52], it is not surprising that bacterial toxins have exploited structural disorder in their structure to enhance the ability to penetrate and damage healthy cells. Structural disorder within toxins has been well characterized and summarized previously [49], and shows toxins utilizing regions of disorder ranging from short stretches within domains (such as in colicin-E9 and calmodulin-sensitive adenylate cyclase), all the way up to larger stretches encompassing much of the entire structure (such as bifunctional hemolysin/adenylate cyclase). The role of this disorder can include targeting and binding with a substrate or receptor, membrane translocation, and/or exposure of the active site.…”

Section: Toxin Structures and Their Role In Defining Macromoleculamentioning

confidence: 99%

Evolutionary Features in the Structure and Function of Bacterial Toxins

Kumar

Feltrup

Kukreja

et al. 2019

Toxins

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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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A novel role of C-terminus in introducing a functionally flexible structure critical for the biological activity of botulinum neurotoxin

Feltrup

Patel

Kumar³

et al. 2018

Sci Rep

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Botulinum neurotoxin (BoNT) is responsible for botulism, a clinical condition resulting in flaccid muscle paralysis and potentially death. The light chain is responsible for its intracellular toxicity through its endopeptidase activity. Available crystal structures of BoNT/A light chains (LCA) are based on various truncated versions (tLCA) of the full-length LCA (fLCA) and do not necessarily reflect the true structure of LCA in solution. The understanding of the mechanism of action, longevity of intoxication, and an improved development of endopeptidase inhibitors are dependent on first having a better insight into the structure of LCA in solution. Using an array of biophysical techniques, we report that the fLCA structure is significantly more flexible than tLCA in solution, which may be responsible for its dramatically higher enzymatic activity. This seems to be achieved by a much stronger, more rapid binding to substrate (SNAP-25) of the fLCA compared to tLCA. These results suggest that the C-terminus of LCA plays a critical role in introducing a flexible structure, which is essential for its biological function. This is the first report of such a massive structural role of the C-terminus of a protein being critical for maintaining a functional state.

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Relevance of Intrinsic Disorder in Protein Structure and Function

Cited by 3 publications

References 118 publications

Catch and Anchor Approach To Combat Both Toxicity and Longevity of Botulinum Toxin A

Catch and Anchor Approach To Combat Both Toxicity and Longevity of Botulinum Toxin A

Evolutionary Features in the Structure and Function of Bacterial Toxins

A novel role of C-terminus in introducing a functionally flexible structure critical for the biological activity of botulinum neurotoxin

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