Abstract
Proteins are essential components of cellular life, as building blocks, but also to guide and execute all cellular processes. Proteins require a three-dimensional folding, which is constantly being challenged by their environment. Challenges including elevated temperatures or redox changes can alter this fold and result in misfolding of proteins or even aggregation. Cells are equipped with several pathways that can deal with protein stress. Together, these pathways are referred to as the protein quality control network. The network comprises degradation and (re)folding pathways that are intertwined due to the sharing of components and by the overlap in affinity for substrates. Here, we will give examples of this sharing and intertwinement of protein degradation and protein folding and discuss how the fate of a substrate is determined. We will focus on the ubiquitylation of substrates and the role of Hsp70 co-chaperones of the DNAJ class in this process.
Highlights
The examples of substrates in the ER associated degradation (ERAD) pathway and protein quality control during translation illustrated that for certain substrates a molecular chaperone is required for ubiquitylation while this is unclear for others
The “holdase” function of DNAJs is well suited to assist E3 ligase function for those substrates that are intrinsically unstable and would misfold, form aggregates or fibrils in the absence of a molecular chaperone. For some of these substrates HSPAs are necessary for degradation but not for ubiquitylation, indicating that they act after the E3 ligase but before proteolysis
The energy provided by the ATP hydroslysis of Hsp70s could facilitate the release of the DNAJ and the E3 ligase from the ubiquitylated substrate (Figure 1B right panel)
Summary
The capacity of the protein quality control network is limited and collapse occurs when the system is overwhelmed This can occur after sudden massive stress including temperature shifts, nutrient deprivation or pathogenic infection (Lee, 1992; Scheuner et al, 2001; Kaufman et al, 2002; Schelhaas et al, 2007; Morimoto, 2008). “normal” conditions in the cell, for example the increased synthesis of proteins during cell cycle progression (Morimoto, 2008) can be considered as physiological protein stress requiring increased folding capacity and adaptations in the quality control network The difference between these two types of protein stress is that the latter is enlisted and that substrate recognition and fate are pre-determined, for example cyclins are degraded upon orchestrated phosphorylation events (Murray, 2004). These accidental clients become unfolded after stress or are intrinsically misfolded (i.e., genetically encoded)
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