Structure of Cu(I)-bound DJ-1 reveals a biscysteinate metal binding site at the homodimer interface: insights into mutational inactivation of DJ-1 in parkinsonism

Puno, M.R., Patel, N.A., Møller, S.G., Robinson, C.V., Moody, P.C.E. and Odell, M. 2013. Structure of Cu(I)-bound DJ-1 reveals a biscysteinate metal binding site at the homodimer interface: insights into mutational inactivation of DJ-1 in parkinsonism. Journal of the American Chemical Society. 135 (43), p. 15974–15977. doi:10.1021/ja406010m

TitleStructure of Cu(I)-bound DJ-1 reveals a biscysteinate metal binding site at the homodimer interface: insights into mutational inactivation of DJ-1 in parkinsonism
AuthorsPuno, M.R., Patel, N.A., Møller, S.G., Robinson, C.V., Moody, P.C.E. and Odell, M.
Abstract

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.

JournalJournal of the American Chemical Society
Journal citation135 (43), p. 15974–15977
Year2013
Digital Object Identifier (DOI)doi:10.1021/ja406010m
Web address (URL)http://pubs.acs.org/doi/abs/10.1021/ja406010m
Publication dates21 Oct 2013

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