WHAT ULTRASTABLE GLOBULAR-PROTEINS TEACH US ABOUT PROTEIN STABILIZATION

Proteins, due to their delicate balance of stabilizing and destabilizi ng interactions, are only marginally stable if physiological condition s are considered as the standard state. Enhanced intrinsic stability o f ''ultrastable'' proteins, e.g., from extremophiles, requires only mi nute local structural changes. Thus, general strategies of stabilizati on are not available for temperature, pH, salt, or pressure adaptation . Mechanisms of enhanced thermal stability involve improved packing or docking of structural elements (domains, subunits), as well as specif ic local interactions, e.g., networks of ion pairs. Relating the struc ture and stability of eye lens crystallins (which do not undergo ally turnover during the life time of an organism), point mutations, nickin g and swapping of domains, grafting of linker peptides between domains , and denaturation-renaturation allowed the cumulative nature of prote in stability and its relation to the hierarchy of protein structure an d folding to be established. In this review, recent results for crysta llins and enzymes from hyperthermophiles will be discussed as models t o illustrate mechanisms of protein stabilization.