Stability and folding of ultrastable proteins: eye lens crystallins and enzymes from thermophiles.

Soluble globular proteins exhibit marginal stabilities, equivalent to only a few weak intermolecular interactions. Extreme conditions in the biosphere, as well as acute physiological stress, require either mutative adaptation or stabilization by accessory proteins or extrinsic factors such as metabolites, cofactors, or compatible solvent components. No general strategies of stabilization have yet been established. However, certain contributions to stability have been elucidated by analyzing extremely stable proteins, such as crystallins from the eye lens, or proteins from hyperthermophilic microorganisms. Relating the structure and stability of homologous proteins from mesophiles and extremophiles, it becomes clear that stability increments may accumulate from 1) local interactions, 2) secondary or supersecondary structure, 3) packing and docking of domains, 4) association of subunits, and 5) conjugation with prosthetic groups, carbohydrate moieties, or nucleic acids, etc. Single and multiple point mutations, nicking and swapping of folding units in domain proteins, grafting of linker peptides between domains, and dissociation-reassociation of oligomeric proteins give insight into the cumulative nature of protein stability and its relation to the hierarchy of protein structure and folding. In this review, beta gamma-crystallins and enzymes from hyperthermophilic microorganisms are used as models to discuss mechanisms of protein stabilization.