On the nature of the optimal form of the holdase‐type chaperone stress response

Abstract

The holdase paradigm of chaperone action involves preferential binding by the chaperone to the unfolded protein state, thereby preventing it from either, associating with other unstable proteins (to form large dysfunctional aggregates), or being degraded by the proteolytic machinery of the cell/organism. In this paper, we examine the necessary physical constraints imposed upon the holdase chaperone response in a cell-like environment and use these limitations to comment on the likely nature of the optimal form of chaperone response in vivo.

Redefining Molecular Chaperones as Chaotropes

“…Holdase chaperones are typically ATP-independent chaperones, that merely associate with non-native client proteins for extended time periods to stabilize them and prevent their aggregation ( Hall, 2020 ). Despite the fact that holdases do not directly fold proteins, their activity is indispensable as they protect vulnerable non-native states from aggregation.…”

Regulation of chaperone function by coupled folding and oligomerization

“…Nonetheless, some ATP-independent chaperones were found to be regulated by major conformational changes, and the transition mechanisms for the activation of ATP-independent chaperones have been classified into three categories ( 5 ): oligomer disassembly [small heat shock protein (sHSP) ( 6 ) and trigger factor (TF) ( 7 – 9 )], order-to-disorder transition {Hsp33 ( 10 ), HdeA [HNS (histone-like nucleoid structuring)–dependent expression A] ( 11 ), and HdeB ( 12 )}, and lack of major conformational change [spheroplast protein Y (Spy) ( 13 , 14 ), seventeen kilodalton protein (Skp) ( 15 ), HSP40 ( 16 ), SecB ( 17 ), and survival factor A (SurA) ( 18 )]. These mechanisms of activation are of major biological importance, because constitutively active chaperones can interfere with protein folding processes and proteostasis due to their high affinity and low specificity for client proteins, thus representing a potential hazard to cells ( 19 – 22 ). An example of these detrimental effects has been reported for a constitutively active variant of the chaperone Hsp33, which lead to accumulation of large amounts of insoluble aggregates and severe growth disadvantages ( 20 ).…”

Cytosolic protein quality control machinery: Interactions of Hsp70 with a network of co-chaperones and substrates

“…56,71 Despite the structural information provided by the Kityk et al study, conclusive details regarding the mechanism by which the chaperones conduct holdase activity remain elusive, particularly given conflicting structural information from Alderson, et al 40,72 Foldase activity is tied to ATP hydrolysis and drives the folding of misfolded, aggregated, or unfolded substrates to the native state. 73 The function of Hsp70 as a foldase is often linked to interactions with the 90-kilo Dalton heat shock protein (Hsp90) by forming a complex capable of remodeling the substrate until it reaches the native state. 74 In this process, once a client is released from Hsp70 during the allosteric cycle, the co-chaperone Hsp70/Hsp90 organizing protein (HOP) transfers the substrate between Hsp70 and Hsp90 as folding progresses towards the native state of the substrate.…”