Chaperone machines for protein folding, unfolding and disaggregation

Abstract

Molecular chaperones are diverse families of multidomain proteins that have evolved to assist nascent proteins to reach their native fold, protect subunits from heat shock during the assembly of complexes, prevent protein aggregation or mediate targeted unfolding and disassembly. Their increased expression in response to stress is a key factor in the health of the cell and longevity of an organism. Unlike enzymes with their precise and finely tuned active sites, chaperones are heavy-duty molecular machines that operate on a wide range of substrates. The structural basis of their mechanism of action is being unravelled (in particular for the heat shock proteins HSP60, HSP70, HSP90 and HSP100) and typically involves massive displacements of 20-30 kDa domains over distances of 20-50 Å and rotations of up to 100°.

Quantitative proteomics and network analysis of SSA1 and SSB1 deletion mutants reveals robustness of chaperone HSP70 network in Saccharomyces cerevisiae

“…While the entire chaperone network is involved in the many biological processes relating to cellular protein homeostasis 10, a sub‐network of HSP70 molecular chaperones are thought to be chiefly responsible for mediating de novo protein folding through a mechanism involving cycles of binding and release of substrate proteins, triggered by ATP and HSP40 cofactors 11. They also have known functions in protein translocation across biological membranes and dissolution of aggregates 12.…”

Reversing deleterious protein aggregation with re-engineered protein disaggregases

“…Therefore, Hsp104 is a relatively poor candidate for rational design. 32 Initially, we hypothesized that the substrate-binding loop regions that line the central channel of Hsp104 31 could be optimized against specific substrates. However, we have noted only subtle rescue phenotypes and more typically detrimental effects when mutating these positions.…”

Small heat shock proteins in ageing and age-related diseases

“…In parallel to UPS and autophagy, a repertoire of chaperone machines, which are denoted according to their molecular weight (HSP60, HSP70, HSP90, HSP100), functions to refold polypeptides which have acquired an erroneous conformation and prevent the aggregation of misfolded intermediates (Saibil 2013). The genome also encodes for small heat shock proteins (sHSPs), with a molecular mass ranging from 12 to 42 kDa (Haslbeck and Vierling 2015).…”