Energy landscape of ALS-related proteins

Protein misfolding and aggregation have been implicated in a number of human diseases.  One of the proteins that we study, human superoxide dismutase (hSOD1), has been implicated in amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease.  As part of a collaborative effort with Jill Zitzewitz and Bob Matthews, we have been studying the

thermodynamics of hSOD1 to better understand the factors leading to oligomerization and toxicity.  By mapping out the energy landscape of the protein from thermodynamic and kinetic studies, we have found that disease-related mutations lead to a preferential increase in the populations of unfolded species which may be prone to aggregation andperhaps responsible for the gain of function.  This is illustrated in thefree-energy diagram in the figure above where the dotted lines represent the landscape for disease-related variants.

Time-resolved FRET spectroscopy of peptides:  Our work going forward is focused on several different areas.  We are interested in the non-native structure persistent in the C-terminal region peptide.  This region is protected against hydrogen exchange in in vivo studies by the Furukawa group.  Time-resolved FRET studies on this peptide show that a collapsed state is populated – this is not observed for other peptides.  We are currently pursuing time-resolved FRET studies on both the peptide and the full-length protein to explore the non-native structure in the unfolded state.