6FOL

Domain II of the human copper chaperone in complex with human Cu,Zn superoxide dismutase

6FOL の概要

• エントリーDOI: 10.2210/pdb6fol/pdb
• 分子名称: Copper chaperone for superoxide dismutase, Superoxide dismutase [Cu-Zn], ZINC ION, ... (6 entities in total)
• 機能のキーワード: heterodimer, copper-chaperone, hsod1, protein maturation, metal binding protein
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 127676.03

構造登録者

Sala, F.A.,Wright, G.S.A.,Antonyuk, S.V.,Garratt, R.C.,Hasnain, S.S. (登録日: 2018-02-07, 公開日: 2019-01-30, 最終更新日: 2024-10-23)

主引用文献

Sala, F.A.,Wright, G.S.A.,Antonyuk, S.V.,Garratt, R.C.,Hasnain, S.S.
Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS.
Plos Biol., 17:e3000141-e3000141, 2019

PubMed Abstract: 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.

PubMed: 30735496
DOI: 10.1371/journal.pbio.3000141

実験手法

X-RAY DIFFRACTION (2.55 Å)