Structural basis for the interaction between DJ-1 and Bcl-X-L

Abstract

DJ-1 is a multifunctional protein associated with Parkinson's disease (PD) and tumorigenesis. In response to ultraviolet B (UVB) irradiation, DJ-1 is translocated into the mitochondria, and its interaction with the mitochondrial protein Bcl-X-L protects cells against death. In this study, we characterized the molecular interaction between DJ-1 and Bcl-X-L by NMR spectroscopy. The NMR chemical shift perturbation data demonstrated that the oxidized but not the reduced form of DJ-1 binds to the predominantly hydrophobic groove surrounded by the BH1-BH3 domains in Bcl-X-L. In addition, our results showed that the C-terminal alpha 8-helix peptide (Cpep) of DJ-1 binds to the pro-apoptotic BH3 peptide-binding hydrophobic groove in Bcl-X-L and, thus, acts as a Bcl-X-L-binding motif. In combination with the NMR chemical shift perturbation data, a refined structural model of the Bcl-X-L/DJ-1 Cpep complex revealed that the binding mode is remarkably similar to that of other Bcl-X-L/pro-apoptotic BH3 peptide complexes. Taken together, our results provide a structural basis for the binding mechanism between DJ-1 and Bcl-X-L, which will contribute to molecular understanding of the role of mitochondrial DJ-1 in Bcl-X-L regulation in response to oxidative stress. (C) 2017 Elsevier Inc. All rights reserved.