Research

Mammalian disaggregation machinery

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. In yeast, bacteria, and plants, a hexameric Hsp104/ClpB can solubilize these disordered aggregates and amyloids, however, curiously, metazoa lack an Hsp104 homolog. Instead, our cells employ a different, less understood machinery to refold protein aggregates – a chaperone system comprised of Hsp110, Hsp70, and Hsp40s.

Chaperone interactions with substrates

The majority of 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; resolve aggregates; or deliver substrates to proteolysis.

The motions that drive protein disaggregation

Cells employ sophisticated quality control systems to ensure that cellular proteins perform their intended functions. Under stress conditions, however, proteins folding can start to go wrong, causing the accumulation of misfolded proteins and formation of toxic protein aggregates. Hsp104/ClpB molecular chaperones can help reverse these toxic effects by forcibly untangling protein aggregates and allowing the client proteins to refold into their native states.

Why NMR?

Magnetic resonance (MR) spectroscopy is a powerful technique for determination of biomolecular structure, characterization of protein-protein interactions, and dynamics studies. It has an unrivaled capacity to obtain atomic-resolution maps of transient protein conformations, structurally characterize interactions between biomolecules, and deeply probe protein dynamics - all of which are critically important for understanding the inner workings of the myriad of complex molecular machines that keep our cells alive.