The role of structural dynamics in the thermal adaptation of hyperthermophilic enzymes

Proteins from hyperthermophilic organisms are evolutionary optimised to adopt functional structures and dynamics under conditions in which their mesophilic homologues are generally inactive or unfolded. Understanding the nature of such adaptation is of crucial interest to clarify the underlying mechanisms of biological activity in proteins. Here we measured NMR residual dipolar couplings of a hyperthermophilic acylphosphatase enzyme at 80 degrees C and used these data to generate an accurate structural ensemble representative of its native state. The resulting energy landscape was compared to that obtained for a human homologue at 37 degrees C, and additional NMR experiments were carried out to probe fast (N-15 relaxation) and slow (H/D exchange) backbone dynamics, collectively sampling fluctuations of the two proteins ranging from the nanosecond to the millisecond timescale. The results identified key differences in the strategies for protein-protein and protein-ligand interactions of the two enzymes at the respective physiological temperatures. These include the dynamical behaviour of a beta-strand involved in the protection against aberrant protein aggregation and concerted motions of loops involved in substrate binding and catalysis. Taken together these results elucidate the structure-dynamics-function relationship associated with the strategies of thermal adaptation of protein molecules.

Automated summary

Understanding the differences in adaptation between proteins from hyperthermophilic organisms and their mesophilic homologues is crucial for unraveling the mechanisms of biological activity in proteins. Researchers measured NMR residual dipolar couplings and performed additional NMR experiments to study the structural and dynamical properties of a hyperthermophilic acylphosphatase enzyme and a human homologue. The results identified key differences in protein-protein and protein-ligand interactions, shedding light on the structure-dynamics-function relationship associated with the thermal adaptation strategies of protein molecules.