PDBsum entry 6fp6

Metal binding protein

PDB id: 6fp6

Contents

Protein chains

(+ 6 more) 153 a.a.

(+ 5 more) 231 a.a.

146 a.a.

Ligands

PPI ×6

GOL

Metals

_ZN ×24

Waters ×75

PDB id:

6fp6

Name:

Metal binding protein

Title:

Complex of human cu,zn sod1 with the human copper chaperone for sod1 in a compact conformation

Structure:

Superoxide dismutase [cu-zn]. Chain: a, c, e, g, i, k, m, o, q, s, u, w. Synonym: superoxide dismutase 1,hsod1. Engineered: yes. Mutation: yes. Copper chaperone for superoxide dismutase. Chain: b, d, f, h, j, l, n, p, r, t, v, x. Synonym: superoxide dismutase copper chaperone. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: sod1. Expressed in: escherichia coli. Expression_system_taxid: 511693. Gene: ccs. Expression_system_taxid: 562

Resolution:

3.00Å R-factor: 0.192 R-free: 0.230

Authors:

F.A.Sala,G.S.A.Wright,S.V.Antonyuk,R.C.Garratt,S.S.Hasnain

Key ref:

F.A.Sala et al. (2019). Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS. PLoS Biol, 17, e3000141. PubMed id: 30735496 DOI: 10.1371/journal.pbio.3000141

Date:

09-Feb-18 Release date: 30-Jan-19

Protein chains

P00441  (SODC_HUMAN) -  Superoxide dismutase [Cu-Zn] from Homo sapiens

Seq: 154 a.a.

Struc: 153 a.a.*

Protein chains

O14618  (CCS_HUMAN) -  Copper chaperone for superoxide dismutase from Homo sapiens

Seq: 274 a.a.

Struc: 231 a.a.*

Protein chain

O14618  (CCS_HUMAN) -  Copper chaperone for superoxide dismutase from Homo sapiens

Seq: 274 a.a.

Struc: 146 a.a.

* PDB and UniProt seqs differ at 5 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chains A, C, E, G, I, K, M, O, Q, S, U, W: E.C.1.15.1.1 - superoxide dismutase.
• Reaction: 2 superoxide + 2 H⁺ = H2O2 + O2
• Cofactor: Fe cation or Mn(2+) or (Zn(2+) and Cu cation)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1371/journal.pbio.3000141

PLoS Biol 17:e3000141 (2019)

PubMed id: 30735496

Molecular recognition and maturation of SOD1 by its evolutionarily destabilised cognate chaperone hCCS.

F.A.Sala, G.S.A.Wright, S.V.Antonyuk, R.C.Garratt, S.S.Hasnain.

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.