Effects of maturation on the conformational free-energy landscape of SOD1.
Robert M. Culik,Ashok Sekhar,Jayashree Nagesh,Harmeen Deol,Jessica A.O. Rumfeldt,Elizabeth M. Meiering,Lewis E. Kay,Lewis E. Kay +7 more
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TLDR
In this paper, the authors examined 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.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 observed in rare conformers of apoSOD12SH; thus, SOD1 maturation may occur via a population-switch mechanism whereby posttranslational modifications select for preexisting structures on the FES. Metallation and oxidation of SOD1 stabilize the native, mature conformation and decrease the number of detected excited conformational states, suggesting that it is the immature forms of the protein that contribute to misfolded conformations in vivo rather than the highly stable enzymatically active dimer.read more
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Visualizing and trapping transient oligomers in amyloid assembly pathways.
TL;DR: Use of methods capable of detecting lowly-populated species within complex mixtures, such as NMR, single particle methods, and mass spectrometry, and chemical and biological tools to bias the amyloid energy landscape towards specific oligomeric states are discussed.
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NMR spectroscopy captures the essential role of dynamics in regulating biomolecular function.
T. Reid Alderson,Lewis E. Kay +1 more
TL;DR: In this article, the authors demonstrate how nuclear magnetic resonance (NMR) spectroscopy provides an essential, dynamic view of structural biology that captures biomolecular motions at atomic resolution.
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Unveiling invisible protein states with NMR spectroscopy
T. Reid Alderson,Lewis E. Kay +1 more
TL;DR: Recent progress toward understanding the roles of sparsely populated, otherwise 'invisible' states present in protein folding and misfolding is reviewed, where NMR has provided unique insight into folding intermediates, transiently misfolded states, and soluble oligomers that precede amyloid fibril formation.
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Superoxide Dismutase 1 in Health and Disease: How a Frontline Antioxidant Becomes Neurotoxic.
Benjamin G. Trist,James B. Hilton,Dominic J. Hare,Dominic J. Hare,Dominic J. Hare,Peter J. Crouch,Kay L. Double +6 more
TL;DR: Current understanding of SOD1 biology from S OD1 genetics through to protein function and stability is summarised.
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Structural Properties and Interaction Partners of Familial ALS-Associated SOD1 Mutants.
Jisen Huai,Zhongjian Zhang +1 more
TL;DR: The goal is to find clues to the possible internal links between structural and functional anomalies of SOD1 mutants, as well as the relationships between their exposed epitopes and interaction partners, in order to help reveal and determine potential diagnostic and therapeutic targets.
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