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, resulting 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.

Structure–Activity Study of Bioisosteric Trifluoromethyl and Pentafluorosulfanyl Indole Inhibitors of the AAA ATPase p97

“…17 Binding to ATP followed by hydrolysis to ADP initiates massive conformational changes in the hexameric p97 that can segregate a bound protein from a macromolecular ligand, including other proteins and membrane segments (Figure 1). 18 As found for other chaperones, 20,21 various forms of cancer, including breast, lung, pancreatic, and colorectal cancer, upregulate p97 as a response to accelerated growth and deteriorating protein quality control. 22,23 This property might render cancer cells more sensitive to p97 inhibitors than normal cells.…”

Translation from the 5′ untranslated region shapes the integrated stress response

“…Stress-resistant expression is a common feature of chaperones and heat shock proteins (65), with the 5′ UTR often necessary and sufficient to reconstitute expression during stress (66, 67). We examined ribosome profiling data (33) for a variety of chaperones to identify non-AUG uORFs in their 5′ UTRs.…”

Hallmarks of therapeutic management of the cystic fibrosis functional landscape

“…In general, analysis of SN physiologic dynamics 134 holds great promise for deepening our understanding of the multiple variables contributing to disease progression in the lung, as a current primary focus, but also the co-morbidities such as CF-related diabetes 135 , pancreatitis 136 , bone disease 137 , or defective spermatogenesis 138 that co-evolve along the patient aging timeline in response to increasing proteostasis challenges in managing not just CFTR but the collapsing proteome 10,22,35,78,79,139–141 .…”