A faulty interaction between SOD1 and hCCS in neurodegenerative disease.
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.
Molecular Biophysics Group, Institute of Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, UK.
Gareth S A
GS
Wright
Molecular Biophysics Group, Institute of Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, UK.
Svetlana V
SV
Antonyuk
Molecular Biophysics Group, Institute of Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, UK.
S Samar
SS
Hasnain
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism; D009154:Mutation; D011485:Protein Binding; D000072105:Superoxide Dismutase-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
C114678:CCS protein, human; D018832:Molecular Chaperones; C000606290:SOD1 protein, human; D000072105:Superoxide Dismutase-1; D015032:Zinc