Files
Document type
ArticleVersion
Published versionPublication date
All rights reserved
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/176729
Altered thiol chemistry in human amyotrophic lateral sclerosis-linked mutants of superoxide dismutase 1
Journal Title
Director/Tutor
Additional contribution
Journal ISSN
Volume Title
Abstract
Neurodegenerative diseases share a common characteristic, the presence of intracellular or extracellular deposits of protein aggregates in nervous tissues. Amyotrophic Lateral Sclerosis (ALS) is a severe and fatal neurodegenerative disorder, which affects preferentially motoneurons. Changes in the redox state of superoxide dismutase 1 (SOD1) are associated with the onset and development of familial forms of ALS. In human SOD1 (hSOD1), a conserved disulfide bond and two free cysteine residues can engage in anomalous thiol/disulfide exchange resulting in non-native disulfides, a hallmark of ALS that is related to protein misfolding and aggregation. Because of the many competing reaction pathways, traditional bulk techniques fall short at quantifying individual thiol/disulfide exchange reactions. Here, we adapt recently developed single-bond chemistry techniques to study individual disulfide isomerization reactions in hSOD1. Mechanical unfolding of hSOD1 leads to the formation of a polypeptide loop held by the disulfide. This loop behaves as a molecular jump rope that brings reactive Cys-111 close to the disulfide. Using force-clamp spectroscopy, we monitor nucleophilic attack of Cys-111 at either sulfur of the disulfide and determine the selectivity of the reaction. Disease-causing mutations G93A and A4V show greatly altered reactivity patterns, which may contribute to the progression of familial ALS.
Related resource
Subject (English)
Citation
Citation
SOLSONA SANCHO, Carles, et al. Altered thiol chemistry in human amyotrophic lateral sclerosis-linked mutants of superoxide dismutase 1. Journal of Biological Chemistry. 2014. Vol. 289, num. 39, pags. 26722-26732. ISSN 0021-9258. [consulted: 8 of October of 2026]. Available at: https://hdl.handle.net/2445/176729