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Most proteins must fold into defined three-dimensional structures to gain functional activity. But in the cellular environment, newly synthesized proteins are at great risk of aberrant folding and aggregation, potentially forming toxic species. To avoid these dangers, cells invest in a complex network of molecular chaperones, which use ingenious mechanisms to prevent aggregation and promote efficient folding. Because protein molecules are highly dynamic, constant chaperone surveillance is required to ensure protein homeostasis (proteostasis). Recent advances suggest that an age-related decline in proteostasis capacity allows the manifestation of various protein-aggregation diseases, including Alzheimer's disease and Parkinson's disease. Interventions in these and numerous other pathological states may spring from a detailed understanding of the pathways underlying proteome maintenance.
Proteins are the most versatile and structurally complex biological macromolecules. They are involved in almost every biological process. Mammalian cells typically express in excess of 10,000 different protein species, which are synthesized on ribosomes as linear chains of up to several thousand amino acids. To function, these chains must generally fold into their 'native state', an ensemble of a few closely related three-dimensional structures1,2. How this is accomplished and how cells ensure the conformational integrity of their proteome in the face of acute and chronic challenges constitute one of the most fundamental and medically relevant problems in biology.
Central to this problem is that proteins must retain conformational flexibility to function, and thus are only marginally thermodynamically stable in their physiological environment. A substantial fraction of all proteins in eukaryotic cells (20-30% of the total in mammalian cells) even seem to be inherently devoid of any ordered three-dimensional structure and adopt folded conformations only after interaction with binding partners3. Aberrant behaviour of some of these metastable proteins, such as tau and α-synuclein, can give rise to the formation of fibrillar aggregates that are associated with dementia and Parkinson's disease. Thus, protein quality control and the maintenance of proteome homeostasis (known as proteostasis) are crucial for cellular and organismal health. Proteostasis is achieved by an integrated network of several hundred proteins4, including, most prominently, molecular chaperones and their regulators, which assist in de novo folding or refolding, and the ubiquitin-proteasome system (UPS) and autophagy system, which mediate the timely removal of irreversibly misfolded and aggregated proteins. Deficiencies in proteostasis...