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 NR, Zitzewitz JA, Bilsel O, Matthews CR. (2019). Nonnative structure in a peptide model of the unfolded state of SOD1: Implications for ALS-linked aggregation. Open Access Publications by UMMS Authors. https://doi.org/10.1074/jbc.RA119.008765. Retrieved from https://escholarship.umassmed.edu/oapubs/3917
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