Metazoan Hsp70-based protein disaggregases: emergence and mechanisms.

Nadinath B Nillegoda,Bernd Bukau

doi:10.3389/fmolb.2015.00057

Abstract

Proteotoxic stresses and aging cause breakdown of cellular protein homeostasis, allowing misfolded proteins to form aggregates, which dedicated molecular machines have evolved to solubilize. In bacteria, fungi, protozoa and plants protein disaggregation involves an Hsp70•J-protein chaperone system, which loads and activates a powerful AAA+ ATPase (Hsp100) disaggregase onto protein aggregate substrates. Metazoans lack cytosolic and nuclear Hsp100 disaggregases but still eliminate protein aggregates. This longstanding puzzle of protein quality control is now resolved. Robust protein disaggregation activity recently shown for the metazoan Hsp70-based disaggregases relies instead on a crucial cooperation between two J-protein classes and interaction with the Hsp110 co-chaperone. An expanding multiplicity of Hsp70 and J-protein family members in metazoan cells facilitates different configurations of this Hsp70-based disaggregase allowing unprecedented versatility and specificity in protein disaggregation. Here we review the architecture, operation, and adaptability of the emerging metazoan disaggregation system and discuss how this evolved.

Highlights

Yeast Hsp110 (Sse1) exhibits reduced affinity for peptide substrate in the presence of ATP, indicating nucleotide binding induces substrate release (Xu et al, 2012). This suggests allosteric coupling between the NBD and SBD of Hsp110 proteins prompting the idea that the nucleotide exchange factor (NEF) could function as a substrate binding/unbinding Hsp70-like chaperone in protein disaggregation
Increased system diversification, versatility and components increases the scope for defects arising in protein quality control processes, with the potential to translate into disease
The substrate spectrum of the metazoan Hsp70-based disaggregase is currently poorly understood in vivo

Summary

Introduction

Toxicities associated with protein misfolding are countered by regulated cellular processes that sequester damaged, sticky and potentially harmful proteins to intracellular protein deposit sites (Taylor et al, 2003; Arrasate et al, 2004; Miller et al, 2015) where protein quality control machineries operate to resolve aggregates (disaggregation) (Parsell et al, 1994; Mogk et al, 1999; Tyedmers et al, 2010; Doyle et al, 2013). This suggests allosteric coupling between the NBD and SBD of Hsp110 proteins prompting the idea that the NEF could function as a substrate binding/unbinding Hsp70-like chaperone in protein disaggregation Such nucleotide dependent substrate release activity was not observed with other Sse specific peptide substrates (Goeckeler et al, 2008). The in vitro activity on amorphous aggregates by human Hsp70-based disaggregases containing heterocomplexed J-proteins is ∼33% less efficient without Hsp110 (Nillegoda et al, 2015) This is reminiscent of the yeast bi-chaperone-based disaggregase system where Hsp110 acts as a NEF, which boosts, but is dispensable for, disaggregation (Glover and Lindquist, 1998; Rampelt et al, 2012). How are multiple Hsp molecules efficiently attracted to one site on the surface of an aggregate? This is the crucial first step for this model

A Central Role for J-proteins in Disaggregase Structure

A J-protein Gearbox Regulates Metazoan Protein Disaggregation Efficacy

Findings

Concluding Remarks