Unknown

Dataset Information

0

Altered thiol chemistry in human amyotrophic lateral sclerosis-linked mutants of superoxide dismutase 1.


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.

SUBMITTER: Solsona C 

PROVIDER: S-EPMC4175315 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

altmetric image

Publications

Altered thiol chemistry in human amyotrophic lateral sclerosis-linked mutants of superoxide dismutase 1.

Solsona Carles C   Kahn Thomas B TB   Badilla Carmen L CL   Álvarez-Zaldiernas Cristina C   Blasi Juan J   Fernandez Julio M JM   Alegre-Cebollada Jorge J  

The Journal of biological chemistry 20140804 39


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  ...[more]

Similar Datasets

| S-EPMC553303 | biostudies-literature
| S-EPMC1413921 | biostudies-literature
| S-EPMC2850267 | biostudies-literature
| S-EPMC4887173 | biostudies-literature
| S-EPMC5016121 | biostudies-literature
| S-EPMC6280858 | biostudies-literature
| S-EPMC10075107 | biostudies-literature
| S-EPMC10270254 | biostudies-literature
| S-EPMC1633719 | biostudies-literature
| S-EPMC6926953 | biostudies-literature