Abstract
A novel approach to reveal intramolecular signal transduction network is proposed in this work. To this end, a new algorithm of network construction is developed, which is based on a new protein dynamics model of energy dissipation. A key feature of this approach is that direction information is specified after inferring protein residue-residue interaction network involved in the process of signal transduction. This enables fundamental analysis of the regulation hierarchy and identification of regulation hubs of the signaling network. A well-studied allosteric enzyme, E. coli aspartokinase III, is used as a model system to demonstrate the new method. Comparison with experimental results shows that the new approach is able to predict all the sites that have been experimentally proved to desensitize allosteric regulation of the enzyme. In addition, the signal transduction network shows a clear preference for specific structural regions, secondary structural types and residue conservation. Occurrence of super-hubs in the network indicates that allosteric regulation tends to gather residues with high connection ability to collectively facilitate the signaling process. Furthermore, a new parameter of propagation coefficient is defined to determine the propagation capability of residues within a signal transduction network. In conclusion, the new approach is useful for fundamental understanding of the process of intramolecular signal transduction and thus has significant impact on rational design of novel allosteric proteins.
Highlights
The structure of a protein is the basis for understanding its function
A thorough knowledge of the principle(s) governing protein dynamics is of fundamental importance for functional study and design of new protein functions
Structures The X-ray diffraction structures of E. coli aspartokinase III were retrieved from Protein Data Bank (PDB) [34]
Summary
The structure of a protein is the basis for understanding its function. the function is governed by its dynamics in most cases. As a classic model for understanding the relationship(s) among protein structure, dynamics and function, allosteric proteins have attracted large attention for decades (for recent reviews see [3,4,5,6]). Intramolecular signal transduction has been proposed as a key concept of protein allostery [4,5,14] and successfully used for redesign of protein functions [15,16]. None of these models describe how the signal is transferred from the regulatory site to the active site upon binding of an effector to the allosteric site. We proposed a new protein dynamics model [17], which considers the signalling process as the result of energy dissipation
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