Identification of an artificial peptide motif that binds and stabilizes reduced human DJ-1

Premkumar, Lakshmanane, Dobaczewska, Malgorzata K. and Riedl, Stefan J. (2011) Identification of an artificial peptide motif that binds and stabilizes reduced human DJ-1. Journal of Structural Biology, 176 3: 414-418. doi:10.1016/j.jsb.2011.08.011

Author Premkumar, Lakshmanane
Dobaczewska, Malgorzata K.
Riedl, Stefan J.
Title Identification of an artificial peptide motif that binds and stabilizes reduced human DJ-1
Journal name Journal of Structural Biology   Check publisher's open access policy
ISSN 1047-8477
Publication date 2011-12
Sub-type Article (original research)
DOI 10.1016/j.jsb.2011.08.011
Volume 176
Issue 3
Start page 414
End page 418
Total pages 5
Place of publication Maryland Heights, MO, U.S.A.
Publisher Academic Press
Collection year 2012
Language eng
Formatted abstract
Although the precise biochemical function of DJ-1 remains unclear, it has been found to exert cytoprotective activity against oxidative stress. Cys106 is central to this function since it has a distinctly low pKa rendering it extremely susceptible for oxidation. This characteristic, however, also poses a severe hindrance to obtain reduced DJ-1 for in vitro investigation. We have developed an approach to produce recombinant human DJ-1 in its reduced form as a bona fide basis for exploring the redox capacities of the protein. We solved the crystal structure of this DJ-1 at 1.56 Å resolution, allowing us to capture Cys106 in the reduced state for the first time. The dimeric structure reveals one molecule of DJ-1 in its reduced state while the other exhibits the characteristics of a mono-oxygenated cysteine. Comparison with previous structures indicates the absence of redox dependent global conformational changes in DJ-1. The capture of reduced Cys106 is facilitated by stabilization within the putative active site achieved through a glutamate side chain. This side chain is provided by a crystallographic neighbor as part of a ‘Leu–Glu’ motif, which was added to the C-terminus of DJ-1. In the structure this motif binds DJ-1 in close proximity to Cys106 through extended hydrophilic and hydrophobic interactions depicting a distinct binding pocket, which can serve as a basis for compound development targeting DJ-1.
Keyword Oxidative stress
Crystal structure of reduced DJ-1
Reduced putative active site cysteine
Active site binding (putative)
Protecting DJ-1 oxidation
Compound template
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ
Additional Notes Available online 27 August 2011.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
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Created: Tue, 06 Sep 2011, 09:27:02 EST by Susan Allen on behalf of Institute for Molecular Bioscience