A versatile chaperone network promoting the aggregation and disaggregation of misfolded proteins

Abstract

Misfolded proteins are sticky and tend to form intracellular aggregates underpinning age‐related deterioration and disease. Normally, multi‐tiered cellular quality control systems monitor and repair protein damage, limiting aggregation. Severe stress however overloads these systems allowing aggregates to accumulate. This activates a cellular machinery which mediates the organized aggregation of misfolded proteins as well as the subsequent solubilisation and refolding and of aggregated proteins. This machinery plays a pivotal role in cell survival under protein folding stress and in counteracting disease and age‐associated cell toxicities.Small heat shock proteins (sHsp) constitute an evolutionary conserved yet diverse family of chaperones acting as first line of defense against proteotoxic stress. The yeast sHsps Hsp42 and Hsp26 promote the storage of misfolded proteins in native‐like conformation which facilitates disaggregation by ATP dependent chaperone systems. In plants, fungi and bacteria the central disaggregation machinery is a powerful bi‐chaperone system comprised by the AAA+ disaggregase Hsp100 (Hsp104, ClpB) and the cooperating Hsp70 chaperone with its co‐chaperones, J‐domain proteins (JDPs) and nucleotide exchange factors (NEFs). Metazoan cells lack Hsp100 disaggregases, but have evolved a potent Hsp70‐based disaggregation machinery which relies on synergistic action of Hsp70 and its co‐chaperones. This activity has broad specificity and can even disassemble amyloid fibrils of α‐synuclein. A different disaggregation strategy has therefore evolved in evolution of metazoa.Support or Funding InformationGerman Research Foundation (DFG)