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http://hdl.handle.net/2445/176729
Title: | Altered thiol chemistry in human amyotrophic lateral sclerosis-linked mutants of superoxide dismutase 1 |
Author: | Solsona Sancho, Carles Kahn, Thomas B. Badilla, Carmen L. Álvarez Zaldiernas, Cristina Blasi Cabús, Joan Fernández, Julio M. Alegre-Cebollada, Jorge |
Keywords: | Esclerosi lateral amiotròfica Enzimologia Cisteïna Química Amyotrophic lateral sclerosis Enzymology Cysteine Chemistry |
Issue Date: | 26-Sep-2014 |
Publisher: | American Society for Biochemistry and Molecular Biology |
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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1074/jbc.M114.565333 |
It is part of: | Journal of Biological Chemistry, 2014, vol. 289, num. 39, p. 26722-26732 |
URI: | http://hdl.handle.net/2445/176729 |
Related resource: | https://doi.org/10.1074/jbc.M114.565333 |
ISSN: | 0021-9258 |
Appears in Collections: | Articles publicats en revistes (Patologia i Terapèutica Experimental) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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672852.pdf | 1.48 MB | Adobe PDF | View/Open |
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