A faulty interaction between SOD1 and hCCS in neurodegenerative disease

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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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
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:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3002593