AMYLOID REMODELING BY Hsp104

Life demands that proteins fold into very precise functional structures. Functional native structure is enciphered by primary sequence (Anfinsen, 1973; Englander et al., 2007). However, native structures are dynamic systems composed of sophisticated networks of weak, mutually supportive contacts that are difficult to establish simultaneously during folding (Bartlett and Radford, 2009; Englander et al., 2007). Thus, folding energy landscapes are often rugged and create challenges for successful folding (Bartlett and Radford, 2009). Polypeptides can become trapped in non-native intermediate states or become diverted into off-pathway states. Even after the completion of folding, cooperative units of native structure, termed foldons , repeatedly unfold and refold (Englander et al., 2007). Moreover, mutation or errors in transcription or translation can yield polypeptides that are less able to form functional structures (Dobson, 2003; Lee et al., 2006). Environmental stress can also disrupt protein folding (Parsell and Lindquist, 1993). Consequently, proteins can fail to fold or fail to remain correctly folded. These failures increase the risk of aggregation. The highly crowded macromolecular environment that cells are forced to maintain to function optimally further accentuates this risk (Dobson, 2003; Ellis and Minton,