Protein misfolding and aggregation have been associated with several age-related neurodegenerative diseases, and our understanding of the molecular underpinnings of these diseases is an ongoing area of scientific investigation. In line with this, chaperones and co-chaperones are implicated in an increasing number of protein-misfolding diseases ( Kim et al., 2013 Kakkar et al., 2014). As a highly conserved cellular quality control system and central arm within the proteostasis network (PN), defects in the human chaperome affect cellular proteome maintenance and repair capacity ( Brehme et al., 2014). A genome-wide survey of conserved functional domains defined by biochemical analyses identified over 300 genes encoding components of the human chaperome, represented by 88 chaperones (27%), of which 50 are ATP-dependent, and 244 co-chaperones (73%) ( Brehme et al., 2014). In addition, there are organelle-specific chaperones of the endoplasmic reticulum (ER) ( Kleizen and Braakman, 2004) and mitochondria (MITO) ( Tatsuta et al., 2005), and tetratricopeptide repeat (TPR)-domain-containing co-chaperone family members ( Hartl and Hayer-Hartl, 2002). The chaperome consists of multiple functional families with a varying number of members, including the heat shock protein (HSP) families HSP100, HSP90, HSP70, HSP60 the chaperonins HSP40 or DNAJ proteins and the small HSPs (sHSPs), where names of each family correspond to the molecular weight of the original founding member ( Hartl and Hayer-Hartl, 2002). Holdases/holders: Molecular chaperones that act in an ATP-independent manner by binding and shielding exposed hydrophobic regions of nascent or misfolded polypeptides as well as folding intermediates to prevent their aggregation or aberrant interaction with cellular proteins. Interactome: The ensemble of molecular interactions in a particular cell at a given point in time, including physical protein-protein interactions.įoldases/folders: Molecular chaperones that utilize ATP in cycles of substrate binding and release in order to support the folding or refolding of their cognate client proteins. Proteome: The ensemble of proteins expressed from protein-coding genes in the human genome by a particular cell at a given point in time, including splice variants and post-translationally modified protein species. Proteostasis: The combined action of processes by which cells maintain a ‘healthy’ proteome, including proper native folding, interaction profile, concentration, and subcellular localization. Taken together, these studies in model systems can inform strategies for therapeutic regulation of chaperone functionality, to manage aging-related proteotoxic stress and to delay the onset of neurodegenerative diseases.Ĭhaperome: The interconnected network of chaperones and co-chaperones that work cooperatively in cellular protein folding, refolding and degradation.Ĭhaperone: Protein that facilitates the folding, refolding and assembly of macromolecular structures, either through the use of ATP in cycles of substrate binding and release, or in an ATP-independent ‘holding’ mode.Ĭo-chaperone: Protein that assists and modulates its cognate chaperone's activity. This review provides a literature-based analysis of these genetic studies and highlights prominent chaperone modifiers of proteotoxicity, which include the HSP70-HSP40 machine and small HSPs. Through the use of suppressor and enhancer screens, key chaperones crucial for proteostasis maintenance have been identified in model organisms that express misfolded disease-related proteins. Understanding the dynamics of chaperone function during aging and disease-related proteotoxic stress could reveal specific chaperone systems that fail to respond to protein misfolding. It has been hypothesized that aging leads to chronic stress on the proteome and that this could underlie many age-associated diseases such as neurodegeneration. Chaperones display dynamic responses to exogenous and endogenous stressors and thus constitute a key component of the proteostasis network (PN), an intricately regulated network of quality control and repair pathways that cooperate to maintain cellular proteostasis. Chaperones and co-chaperones enable protein folding and degradation, safeguarding the proteome against proteotoxic stress.

Chaperone protein