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PDBsum entry 6fp6
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Metal binding protein
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PDB id
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6fp6
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Contents |
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(+ 6 more)
153 a.a.
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(+ 5 more)
231 a.a.
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146 a.a.
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References listed in PDB file
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Key reference
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Title
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Molecular recognition and maturation of sod1 by its evolutionarily destabilised cognate chaperone hccs.
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Authors
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F.A.Sala,
G.S.A.Wright,
S.V.Antonyuk,
R.C.Garratt,
S.S.Hasnain.
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Ref.
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PLoS Biol, 2019,
17,
e3000141.
[DOI no: ]
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PubMed id
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Abstract
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Superoxide dismutase-1 (SOD1) maturation comprises a string of posttranslational
modifications which transform the nascent peptide into a stable and active
enzyme. The successive folding, metal ion binding, and disulphide acquisition
steps in this pathway can be catalysed through a direct interaction with the
copper chaperone for SOD1 (CCS). This process confers enzymatic activity and
reduces access to noncanonical, aggregation-prone states. Here, we present the
functional mechanisms of human copper chaperone for SOD1 (hCCS)-catalysed SOD1
activation based on crystal structures of reaction precursors, intermediates,
and products. Molecular recognition of immature SOD1 by hCCS is driven by
several interface interactions, which provide an extended surface upon which
SOD1 folds. Induced-fit complexation is reliant on the structural plasticity of
the immature SOD1 disulphide sub-loop, a characteristic which contributes to
misfolding and aggregation in neurodegenerative disease. Complexation
specifically stabilises the SOD1 disulphide sub-loop, priming it and the active
site for copper transfer, while delaying disulphide formation and complex
dissociation. Critically, a single destabilising amino acid substitution within
the hCCS interface reduces hCCS homodimer affinity, creating a pool of hCCS
available to interact with immature SOD1. hCCS substrate specificity,
segregation between solvent and biological membranes, and interaction transience
are direct results of this substitution. In this way, hCCS-catalysed SOD1
maturation is finessed to minimise copper wastage and reduce production of
potentially toxic SOD1 species.
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