Understanding
Molecular Chaperones
Proteins are often thought of as highly specialized machines that perform well-defined biochemical tasks: enzymes catalyze reactions, transcription factors recognize specific DNA sequences, and signaling proteins relay defined molecular cues. Molecular chaperones represent a fundamentally different class of proteins. Rather than acting on a single substrate or reaction, chaperones operate as central hubs of cellular proteostasis, coordinating the folding, stabilization, and recovery of hundreds of structurally diverse client proteins.
Among these, the Hsp70 chaperone system—represented in bacteria by the protein DnaK—plays a particularly central role. DnaK must recognize a wide range of partially folded or misfolded protein states, coordinate with multiple regulatory partners such as the co-chaperone DnaJ and the nucleotide exchange factor GrpE, and respond dynamically to changes in cellular conditions such as heat stress or proteome imbalance. How a single molecular machine can robustly service hundreds of distinct proteins while functioning within a network of cooperating regulators remains a fundamental open question in proteostasis biology
A key challenge in studying multifunctional proteins such as chaperones is that many distinct molecular processes contribute to their overall activity. Mutations may influence ATP hydrolysis, client binding, conformational dynamics, or interactions with regulatory partners. In large-scale mutational datasets, these effects often overlap, making it difficult to infer the underlying mechanisms directly.
To address this, we integrate experimental data across multiple conditions and apply dimensionality-reduction approaches to identify underlying functional modules within the chaperone sequence. These analyses allow us to extract latent patterns in the data and identify groups of residues that cooperate to support distinct aspects of chaperone function, such as global proteome stabilization, network coordination, or client-specific folding rescue.
Engineering chaperones for biotechnology and medicine
Beyond revealing the principles of proteostasis, our work aims to enable the rational engineering of chaperones for practical applications. Because chaperones influence the folding and stability of large numbers of proteins, they represent powerful tools for reshaping cellular protein homeostasis. Engineered chaperones could enhance the folding of difficult-to-express proteins in biotechnology, improve the stability and yield of recombinant enzymes and therapeutic proteins, and help cells tolerate proteotoxic stress during industrial fermentation or synthetic biology applications. At the same time, many human diseases—including neurodegenerative disorders and certain inherited metabolic conditions—arise from protein misfolding and aggregation. By understanding how chaperone sequence determines client recognition and network interactions, it may become possible to design chaperone variants that more effectively stabilize vulnerable proteins or suppress toxic aggregation.
Our long-term vision is that quantitative maps of chaperone sequence–function relationships will enable the development of programmable proteostasis systems that can be tuned for both biotechnological and therapeutic purposes.