Novel Human Chaperone Mechanisms Counteracting Protein Misfolding and Aggregation in the Cell

Introduction

Molecular chaperones are vital for maintaining proteostasis by protecting our cells from the deleterious effects of protein misfolding and aggregation. The diverse ~50-chaperone J-domain protein (JDP, Hsp40) family acts as cells’ first line of defense, binding and remodeling non-natively folded proteins and facilitating their transfer to downstream chaperones.

Recent Discoveries

Recent discoveries from our lab have shown that JDP function is far more complex than previously described. We have identified:

1. A novel mode of regulation by which DNAJB1 coordinates amyloid disaggregation.
2. A new mechanism by which class A JDPs recognize destabilized proteins.

Based on these findings and the sheer diversity of human JDPs, we propose that these chaperones employ many additional, yet-to-be-discovered mechanisms to carry out their vital cellular roles.

Importance of Understanding JDPs

Obtaining a structural and functional understanding of these chaperones is crucial, as mutations in JDPs have been linked to many pathologies, including:

• Myopathies
• Neurodegenerative diseases
• Metabolic disorders

Here, we aim to uncover these novel JDP functional mechanisms, determine their role in addressing diverse proteomic challenges, and characterize how their malfunction leads to disease.

Challenges in Studying JDPs

The study of JDPs has proven challenging due to:

• The dynamic nature of these chaperones
• Their transient interactions with clients
• The instability of misfolded proteins

Methodology

The advanced methyl-TROSY NMR techniques used in my lab are ideally suited for such large and dynamic systems. Furthermore, we have developed new NMR and biophysical assays that allow the monitoring of chaperone interactions with misfolded and aggregation-prone substrates in real time.

Project Goals

Using these approaches, this project will unveil the structures and functional mechanisms of the diverse human JDPs. This will introduce fundamental new concepts into the chaperone field and pave the way for therapeutic strategies targeting protein misfolding and aggregation diseases.