The Chemical Biology of Molecular Chaperones--Implications for Modulation of Proteostasis

Abstract

Protein homeostasis (proteostasis) is inextricably tied to cellular health and organismal lifespan. Aging, exposure to physiological and environmental stress, and expression of mutant and metastable proteins can cause an imbalance in the protein-folding landscape, which results in the formation of non-native protein aggregates that challenge the capacity of the proteostasis network (PN), increasing the risk for diseases associated with misfolding, aggregation, and aberrant regulation of cell stress responses. Molecular chaperones have central roles in each of the arms of the PN (protein synthesis, folding, disaggregation, and degradation), leading to the proposal that modulation of chaperone function could have therapeutic benefits for the large and growing family of diseases of protein conformation including neurodegeneration, metabolic diseases, and cancer. In this review, we will discuss the current strategies used to tune the PN through targeting molecular chaperones and assess the potential of the chemical biology of proteostasis.

Keywords: aggregation; heat shock protein; pharmacology; protein folding; small molecule modulators.

Figure 1. Molecular chaperones offer a multi-dimensional approach to pharmacological modulation of the proteostasis network (PN)

Representative molecular chaperones that respectively support each of these components are illustrated. Molecular chaperones are generically represented as yellow circles. The smaller blue, green or red circles represent a pharmacological reagent that impacts synthesis, maintenance, or degradation respectively.

Figure 2. The Hsp70 folding cycle

Hsp70 relies on a complex collection of co-chaperones and nucleotide exchange factors (NEFs) to determine both activity level and substrate specificity. The relative ratio of co-chaperones and NEFs serves as a means to fine-tune the PN, and therefore targeting these protein-protein interactions remains an attractive approach to pharmacological modulation.

Figure 3. Hsp90 and its pharmacological modulators

The structure of the yeast Hsp90 homolog in ribbon presentation. The image represents half of the Hsp90 dimer, which is shown in complex with an ATP molecule. The three respective domains are labeled and color-coded. The ATP molecule is represented in sphere form. The image was generated with Pymol using structure PDB 2CG9. Representative chemical scaffolds for Hsp90 modulators are included, and arrows indicate binding sites.

Figure 4. Hsp70 and its pharmacological modulators

The structure of DnaK, the bacterial homolog of Hsp70 in ribbon presentation, bound to ADP. The ATP- and substrate-binding domains are labeled and color-coded. ADP is represented in sphere form. The image was generated with Pymol using structure PDB 2KHO. Representative chemical scaffolds for Hsp70 modulators are included, and arrows indicate binding sites.

Figure 5. The chaperonin family and its pharmacological modulators

The structure of GroEL, the bacterial homolog of Hsp60 in ribbon presentation. ATP is represented in sphere form. The image was generated with Pymol using structure PDB 4AB2. The top-left portion of the panel displays an overhead view that highlights the substrate-binding cavity. The top-right portion of the panel displays a side view, which more clearly shows the ATP-binding site. The structure of an individual subunit of GroEL is shown in the bottom right. Representative chemical scaffolds for chaperonin modulators are included, and arrows indicate binding sites.