Effects of maturation on the conformational free-energy landscape of SOD1

Proceedings of the National Academy of Sciences of the United States of America
Robert M CulikLewis E Kay

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating fatal syndrome characterized by very rapid degeneration of motor neurons. A leading hypothesis is that ALS is caused by toxic protein misfolding and aggregation, as also occurs in many other neurodegenerative disorders, such as prion, Alzheimer's, Parkinson's, and Huntington's diseases. A prominent cause of familial ALS is mutations in the protein superoxide dismutase (SOD1), which promote the formation of misfolded SOD1 conformers that are prone to aberrant interactions both with each other and with other cellular components. We have shown previously that immature SOD1, lacking bound Cu and Zn metal ions and the intrasubunit disulfide bond (apoSOD12SH), has a rugged free-energy surface (FES) and exchanges with four other conformations (excited states) that have millisecond lifetimes and sparse populations on the order of a few percent. Here, we examine further states of SOD1 along its maturation pathway, as well as those off-pathway resulting from metal loss that have been observed in proteinaceous inclusions. Metallation and disulfide bond formation lead to structural transformations including local ordering of the electrostatic loop and native dimerization that are observe...Continue Reading

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Citations

Nov 26, 2019·Quarterly Reviews of Biophysics·Gareth S A WrightS Samar Hasnain
Aug 15, 2020·Biochemical Society Transactions·Gareth S A Wright
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Jan 9, 2022·Scientific Reports·Mariusz BerdyńskiMagdalena Kuźma-Kozakiewicz

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