Allostery is ubiquitous in biological systems. Virtually any protein may be deemed allosteric. However, the extent to which allosteric communication pathways are "conserved" within protein orthologs remains an open question of great interest. Similarity between protein structures does not necessarily imply similar functionality, and the protein function can be significantly affected by allosteric modulators. Thus, structure-function relationships responsible for allosteric mechanisms can be rather complex. In fact, the notion that similar protein structures imply similar allosteric pathways has been recently challenged by various research groups, suggesting that allosteric communication in protein orthologs is system specific.
To what extent can the allosteric signaling mechanism change across a protein family? The answer to this question must account for the fact that differences in allosteric communication between protein homologs can occur at different levels of the signaling pathways, involving both direct inter-residue contacts and collective motions of protein domains. This advocates for a detailed knowledge of communication pathways that can be explored by atomistic simulations and direct comparisons to experimental data. Implementing such a synergistic approach, we have characterized the allosteric pathways in two different imidazole glycerol phosphate synthase (IGPS) enzymes from two different organisms, the Thermotoga maritima bacteria (right side of the cover) and the Saccharomyces cerevisiae yeast (left side of the cover).
The cover image for the January 4 issue of Biophysical Journal depicts the primary paths of allosteric signals in the two enzymes. Allostery enables communication between two distant active sites, which are essential for catalytic activity in the two IGPS enzymes. In fact, these enzymes (featuring two different evolutionary paths) exploit the same allosteric activation despite significant differences in their primary sequences and secondary structures.
Our study shows that the early time dynamics that initiate allosteric communication (depicted with the granulated paint brush smears) are different in the two enzymes, resulting in distinct allosteric pathways. The allosteric mechanisms are tailored to allow the two enzymes to optimally function in their natural environments (depicted in the background of the two protein cartoons). The thermophilic bacteria exhibit robust functionality at high temperatures, whereas the Saccharomyces yeast functions at room temperature. We find that their allosteric mechanisms involve significant differences in both collective motions and inter-residue interactions, although their catalytic function is equally modulated by the allosteric effector. This is a direct consequence of their different primary sequences, with different types of collective motions induced by the effector, probably resulting from the adaptation of the two enzymes to their different native environments.
- Federica Maschietto, Aria Gheeraert, Andrea Piazzi, Victor S. Batista, and Ivan Rivalta