Available Positions

Almost all proteins depend on a well-defined three-dimensional structure to obtain their functionality. In order to prevent misfolding, aggregation, and the generation of toxic species, the process of protein folding in the cell is often guided by molecular chaperones. These complex protein networks either interact with substrate polypeptides to help them fold; unfold misfolded species; dissolve aggregates; or deliver substrates to proteolysis. Very little structural information, however, is available regarding how chaperones bind their substrates or the manner in which they protect proteins from misfolding and aggregation. 

This lack of information arises from the highly dynamic nature of chaperone-substrate complexes – a trait that prevents their characterization by traditional structural techniques, but fortunately for us, makes them great targets for NMR spectroscopy.

In this project we will use solution-state NMR to probe the molecular interactions between hundreds-of-kilodalton large chaperone complexes and “client” proteins, as well as the structural and dynamic features of these complexes

Protein disaggregases hold the potential to reverse protein aggregation and amyloid fibril formation – conditions that have been identified in an increasing number of debilitating, and ultimately fatal neurodegenerative disorders. While the proteins forming the disaggregation machinery have been identified, the mechanism by which they function is currently unknown. 

By using advanced NMR structural approaches, combined with biochemical functional assays, we plan to uncover this mechanism and understand the role of each chaperone in this vital cellular process.

The Hsp70 chaperone is of prime importance to cancer biology; supporting proliferative growth and stress survival, blocking apoptosis, and fighting protein aggregation caused by aneuploidy or mutation. One central cancer-related substrate of the Hsp70 system is the p53 tumor suppressor protein, in both wild-type and mutant forms, which interacts with the Hsp70 system for (re)folding, stabilization, and degradation. The molecular basis of these interactions and pathway triaging, however, are unknown. This project therefore aims to characterize the roles these molecular chaperones play in cancer pathology.

Almost all proteins depend on a well-defined three-dimensional structure to obtain their functionality. In order to prevent misfolding, aggregation, and the generation of toxic species, the process of protein folding in the cell is often guided by molecular chaperones. These complex protein networks either interact with substrate polypeptides to help them fold; unfold misfolded species; dissolve aggregates; or deliver substrates to proteolysis. Very little structural information, however, is available regarding how chaperones bind their substrates or the manner in which they protect proteins from misfolding and aggregation. 

This lack of information arises from the highly dynamic nature of chaperone-substrate complexes – a trait that prevents their characterization by traditional structural techniques, but fortunately for us, makes them great targets for NMR spectroscopy.

In this project we will use solution-state NMR to probe the molecular interactions between hundreds-of-kilodalton large chaperone complexes and “client” proteins, as well as the structural and dynamic features of these complexes

The Hsp70 chaperone is of prime importance to cancer biology; supporting proliferative growth and stress survival, blocking apoptosis, and fighting protein aggregation caused by aneuploidy or mutation. One central cancer-related substrate of the Hsp70 system is the p53 tumor suppressor protein, in both wild-type and mutant forms, which interacts with the Hsp70 system for (re)folding, stabilization, and degradation. The molecular basis of these interactions and pathway triaging, however, are unknown. This project therefore aims to characterize the roles these molecular chaperones play in cancer pathology.