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 α8-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.