Wright, Gareth SA ORCID: 0000-0002-3756-9634, Antonyuk, Svetlana V
ORCID: 0000-0002-2779-9946 and Hasnain, S Samar
(2016)
A faulty interaction between SOD1 and hCCS in neurodegenerative disease.
SCIENTIFIC REPORTS, 6 (1).
27691-.
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A faulty interaction between SOD1 and hCCS in neurodegenerative disease.pdf - Published version Download (1MB) |
Abstract
A proportion of Amyotrophic lateral sclerosis (ALS) cases result from impaired mutant superoxide dismutase-1 (SOD1) maturation. The copper chaperone for SOD1 (hCCS) forms a transient complex with SOD1 and catalyses the final stages of its maturation. We find that a neurodegenerative disease-associated hCCS mutation abrogates the interaction with SOD1 by inhibiting hCCS zinc binding. Analogously, SOD1 zinc loss has a detrimental effect on the formation, structure and disassociation of the hCCS-SOD1 heterodimer. This suggests that hCCS functionality is impaired by ALS mutations that reduce SOD1 zinc affinity. Furthermore, stabilization of wild-type SOD1 by chemical modification including cisplatination, inhibits complex formation. We hypothesize that drug molecules designed to stabilize ALS SOD1 mutants that also target the wild-type form will lead to characteristics common in SOD1 knock-outs. Our work demonstrates the applicability of chromatographic SAXS when studying biomolecules predisposed to aggregation or dissociation; attributes frequently reported for complexes involved in neurodegenerative disease.
Item Type: | Article |
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Uncontrolled Keywords: | Humans, Amyotrophic Lateral Sclerosis, Zinc, Molecular Chaperones, Binding Sites, Protein Binding, Mutation, Superoxide Dismutase-1 |
Depositing User: | Symplectic Admin |
Date Deposited: | 28 Jul 2016 13:42 |
Last Modified: | 19 Jan 2023 07:32 |
DOI: | 10.1038/srep27691 |
Related URLs: | |
URI: | https://livrepository.liverpool.ac.uk/id/eprint/3002593 |