Yeast Protein Breaks up Amyloid Fibrils and Disordered Protein Clumps In Different Ways

Several fatal brain disorders, including Parkinson’s disease, are connected by the misfolding of specific proteins into disordered clumps and stable, insoluble fibrils called amyloid. Amyloid fibrils are hard to break up due to their stable, ordered structure. For example, a-synuclein forms amyloid fibrils that accumulate in Lewy Bodies in Parkinson’s disease. By contrast, protein clumps that accumulate in response to environmental stress, such as heat shock, possess a less stable, disordered architecture.

Hsp104, an enzyme from yeast, breaks up both amyloid fibrils and disordered clumps. In the most recent issue of Cell, James Shorter, PhD, assistant professor of Biochemistry and Biophysics, and colleagues from the Perelman School of Medicine, University of Pennsylvania, show that Hsp104 switches mechanism to break up amyloid versus disordered clumps. For stable amyloid-type structures, Hsp104 needs all six of its subunits, which together make a hexamer, to pull the clumps apart. By contrast, for the more amorphous, non-amyloid clumps, Hsp104 required only one of its six subunits.