Complexes formed between heat shock protein 70 (Hsp70) and tetratricopeptide repeat (TPR) co-chaperones direct Hsp70's various activities during quality control. However, the molecular mechanisms that influence which TPR co-chaperone will bind with Hsp70 remain uncharacterized. Our long term goal is to understand how the combinatorial assembly of TPR co-chaperones with Hsp70 drives protein quality control decisions. The objective of this proposal is to gain a molecular-level understanding of these protein-protein interactions using a suite of chemical and biochemical approaches. We hypothesize that each TPR co-chaperone maintains a unique set of interactions with Hsp70. In preliminary studies, we developed the first chemical inhibitors of an Hsp70-TPR co-chaperone complex, derivatives of the natural product spergualin. Accordingly, this proposal is innovative because these probes provide the unique opportunity to transiently perturb interactions between Hsp70 and TPR co-chaperones, thus facilitating studies on protein quality control complexes associated with human disease. With this promising preliminary data, we propose two specific aims to test our central hypothesis: (1) characterize interactions between Hsp70 and TPR co-chaperones and (2) characterize the inhibition of Hsp70-TPR co-chaperone complexes using spergualin analogs. Completion of these studies will help clarify the roles of individual Hsp70-TPR protein complexes implicated in diseases of protein misfolding. Public Health Relevance: Dysfunction of protein homeostasis is directly linked to many diseases, including cancer and neurodegeneration. An understanding of protein quality control will provide insights into the mechanisms that contribute to disease and, potentially, provide new opportunities for therapies.
Dysfunction of protein homeostasis is directly linked to many diseases, including cancer and neurodegeneration. An understanding of protein quality control will provide insights into the mechanisms that contribute to disease and, potentially, provide new opportunities for therapies. PUBLIC HEALTH RELEVANCE: Dysfunction of protein homeostasis is directly linked to many diseases, including cancer and neurodegeneration. Therefore, the proposed research is significant and revenant to public health because it explores how protein-protein interactions between heat shock protein 70 and tetratricopeptide repeat co-chaperones govern cellular protein quality control. A better understanding of protein quality control is expected to provide insights into the mechanisms that contribute to human disease and, potentially, provide new opportunities for therapies.
| Assimon, Victoria A; Southworth, Daniel R; Gestwicki, Jason E (2015) Specific Binding of Tetratricopeptide Repeat Proteins to Heat Shock Protein 70 (Hsp70) and Heat Shock Protein 90 (Hsp90) Is Regulated by Affinity and Phosphorylation. Biochemistry 54:7120-31 |
| Assimon, Victoria A; Shao, Hao; Garneau-Tsodikova, Sylvie et al. (2015) Concise Synthesis of Spergualin-Inspired Molecules With Broad-Spectrum Antibiotic Activity. Medchemcomm 6:912-918 |
| Connarn, Jamie N; Assimon, Victoria A; Reed, Rebecca A et al. (2014) The molecular chaperone Hsp70 activates protein phosphatase 5 (PP5) by binding the tetratricopeptide repeat (TPR) domain. J Biol Chem 289:2908-17 |
| Smith, Matthew C; Scaglione, K Matthew; Assimon, Victoria A et al. (2013) The E3 ubiquitin ligase CHIP and the molecular chaperone Hsc70 form a dynamic, tethered complex. Biochemistry 52:5354-64 |
