Department of Biochemistry and Molecular Pharmacology; Graduate School of Biomedical Sciences
Amino Acids, Peptides, and Proteins | Biochemistry | Biophysics | Enzymes and Coenzymes | Genetic Phenomena | Molecular and Cellular Neuroscience | Molecular Biology | Nervous System Diseases | Structural Biology
Dozens of mutations throughout the sequence of the gene encoding superoxide dismutase 1 (SOD1) have been linked to toxic protein aggregation in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). A parsimonious explanation for numerous genotypes resulting in a common phenotype would be mutation-induced perturbation of the folding free-energy surface that increases the populations of high-energy states prone to aggregation. The absence of intermediates in the folding of monomeric SOD1 suggests that the unfolded ensemble is a potential source of aggregation. To test this hypothesis, here we dissected SOD1 into a set of peptides end-labeled with FRET probes to model the local behavior of the corresponding sequences in the unfolded ensemble. Using time-resolved FRET, we observed that the peptide corresponding to the loop VII-beta8 sequence at the SOD1 C-terminus was uniquely sensitive to denaturant. Utilizing a two-dimensional form of maximum entropy modeling, we demonstrate that the sensitivity to denaturant is the surprising result of a two-state-like transition from a compact to an expanded state. Variations of the peptide sequence revealed that the compact state involves a nonnative interaction between the disordered N-terminus and the hydrophobic C-terminus of the peptide. This nonnative intramolecular structure could serve as a precursor for intermolecular association and result in aggregation associated with ALS. We propose that this precursor would provide a common molecular target for therapeutic intervention in the dozens of ALS-linked SOD1 mutations.
Maximum Entropy Modeling, amyotrophic lateral sclerosis (ALS) (Lou Gehrig disease), fluorescence resonance energy transfer (FRET), peptides, protein folding, protein misfolding, superoxide dismutase (SOD)
Rights and Permissions
© 2019 The Author(s). Paper in Press version posted as allowed by the publisher's author rights policy at http://www.jbc.org/site/misc/edpolicy.xhtml#copyright.
DOI of Published Version
J Biol Chem. 2019 Jul 24. pii: jbc.RA119.008765. doi: 10.1074/jbc.RA119.008765. [Epub ahead of print] Link to article on publisher's site
The Journal of biological chemistry
Cohen, Noah R.; Zitzewitz, Jill A.; Bilsel, Osman; and Matthews, C. Robert, "Nonnative structure in a peptide model of the unfolded state of SOD1: Implications for ALS-linked aggregation" (2019). Open Access Articles. 3917.
Amino Acids, Peptides, and Proteins Commons, Biochemistry Commons, Biophysics Commons, Enzymes and Coenzymes Commons, Genetic Phenomena Commons, Molecular and Cellular Neuroscience Commons, Molecular Biology Commons, Nervous System Diseases Commons, Structural Biology Commons