However, concrete evidence of an involvement of molecular chaperones in mammalian prion replication, although proposed 16, is missing, and whether molecular chaperones play a role in the stabilization and/or protection of IDPs remains uncertain. At least in yeast, it is now widely accepted that molecular chaperones play an essential role in prion replication 9, 10 by governing the inheritance and maintenance of yeast prions, and in some cases their elimination by chaperone overexpression 11– 15. Notable examples include prions that can adopt multiple, distinct, three-dimensional structures 3– 5, and an ever-increasing number of intrinsically disordered proteins (IDPs), which feature large regions of random coil or lack a defined structure altogether 6– 8. While most proteins adopt a defined three-dimensional structure, several exceptions are known to exist. Challenging the capacity of this proteostasis network increases the risk of human diseases associated with protein misfolding and aggregation 1. To accomplish this, cells have evolved a sophisticated network of protein quality control machines, consisting of molecular chaperones and proteases, which monitor the folding of proteins and their assembly into functional complexes, and selectively remove excess and damaged proteins from the cell.
Consequently, maintaining protein homeostasis (proteostasis) is essential for cell and organismal health 2. While the protein folding information is encoded within the nascent polypeptide chain, newly synthesized polypeptides (or those imported into organelles) are prone to misfolding, causing aggregation and formation of other toxic species 1. The vast majority of proteins must fold correctly in order to gain functional activity. Furthermore, while a decline of this network is detrimental to cell and organismal health, a controlled perturbation of the proteostasis network may offer new therapeutic avenues against human diseases. Hence, molecular chaperones are the major component of the proteostasis network that guards and protects the proteome from damage. An emerging theme is that most of these chaperones do not work alone, but instead function together with other chaperone systems to maintain the proteome. Here, we review our current understanding of ATP-dependent molecular chaperones that harness the energy of ATP binding and hydrolysis to fuel their chaperone functions. While molecular chaperones and proteases are traditionally associated with protein quality control inside the cell, it is now apparent that molecular chaperones not only promote protein folding in the “forward” direction by facilitating folding and preventing misfolding and aggregation, but also facilitate protein unfolding and even disaggregation resulting in the recovery of functional protein from aggregates. Proteins must adopt a defined three-dimensional structure in order to gain functional activity, or must they? An ever-increasing number of intrinsically disordered proteins and amyloid-forming polypeptides challenge this dogma.
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