3SF8

Structural insights into thiol stabilization of DJ-1

Summary for 3SF8

• Entry DOI: 10.2210/pdb3sf8/pdb
• Descriptor: Protein DJ-1 (3 entities in total)
• Functional Keywords: oxidative stress, redox regulation, cysteine oxidation, protecting dj-1 oxidation, reduced dj-1, class i glutamine amidotransferase family, cytoprotective activity against oxidative stress; cysteine sulfenic acid modification, hydrolase, oncoprotein, unknown function
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: Q99497 Q99497
• Total number of polymer chains: 2
• Total formula weight: 40334.64

Authors

Premkumar, L.,Dobaczewska, M.K.,Riedl, S.J. (deposition date: 2011-06-13, release date: 2011-10-05, Last modification date: 2024-11-27)

Primary citation

Premkumar, L.,Dobaczewska, M.K.,Riedl, S.J.
Identification of an artificial peptide motif that binds and stabilizes reduced human DJ-1.
J.Struct.Biol., 176:414-418, 2011

PubMed 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 pK(a) 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 1.56Å 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.

PubMed: 21893204
DOI: 10.1016/j.jsb.2011.08.011

Experimental method

X-RAY DIFFRACTION (1.56 Å)