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The Parkinsonism-associated protein DJ-1 has been suggested to activate the Cu-Zn superoxide dismutase (SOD1) by providing its copper cofactor. The structural and chemical means by which DJ-1 could support this function is unknown. In this study, we characterize the molecular interaction of DJ-1 with Cu(I). Mass spectrometric analysis indicates binding of one Cu(I) ion per DJ-1 homodimer. The crystal structure of DJ-1 bound to Cu(I) confirms metal coordination through a docking accessible biscysteinate site formed by juxtaposed cysteine residues at the homodimer interface. Spectroscopy in crystallo validates the identity and oxidation state of the bound metal. The measured subfemtomolar dissociation constant (Kd = 6.41 × 10(-16) M) of DJ-1 for Cu(I) supports the physiological retention of the metal ion. Our results highlight the requirement of a stable homodimer for copper binding by DJ-1. Parkinsonism-linked mutations that weaken homodimer interactions will compromise this capability.

Original publication

DOI

10.1021/ja406010m

Type

Journal article

Journal

J Am Chem Soc

Publication Date

30/10/2013

Volume

135

Pages

15974 - 15977

Keywords

Binding Sites, Copper, Crystallography, X-Ray, Cysteine, Humans, Intracellular Signaling Peptides and Proteins, Mass Spectrometry, Metals, Models, Molecular, Mutation, Oncogene Proteins, Parkinson Disease, Protein Conformation, Protein Deglycase DJ-1, Spectrometry, Mass, Electrospray Ionization, Superoxide Dismutase, Superoxide Dismutase-1