Structural and biochemical analysis of Bcl-2 interaction with the hepatitis B virus protein HBx

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 8; pp. 2074 - 2079
• Main Authors: Jiang, Tianyu, 蒋天宇, Liu, Minhao, 刘旻昊, Wu, Jianping, 吴建平, Shi, Yigong, 施一公
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 23.02.2016; National Acad Sciences
• Subjects: Amino Acid Motifs; Apoptosis; Biochemical analysis; Biological Sciences; Carcinogenesis; Crystallography, X-Ray; Hepatitis; Hepatitis B; Hepatitis B virus; Hepatitis B virus - chemistry; Hepatitis B virus - genetics; Hepatitis B virus - metabolism; Humans; Ions; Protein Binding; Proteins; Proto-Oncogene Proteins c-bcl-2 - chemistry; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Structural analysis; Trans-Activators - chemistry; Trans-Activators - genetics; Trans-Activators - metabolism; Bcl-2; crystal structure; apoptosis; hepatitis B virus
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1525616113

HBx is a hepatitis B virus protein that is required for viral infectivity and replication. Anti-apoptotic Bcl-2 family members are thought to be among the important host targets of HBx. However, the structure and function of HBx are poorly understood and the molecular mechanism of HBx-induced carcinogenesis remains unknown. In this study, we report biochemical and structural characterization of HBx. The recombinant HBx protein contains metal ions, in particular iron and zinc. A BH3-like motif in HBx (residues 110–135) binds Bcl-2 with a dissociation constant of ∼193 μM, which is drastically lower than that for a canonical BH3 motif from Bim or Bad. Structural analysis reveals that, similar to other BH3 motifs, the BH3-like motif of HBx adopts an amphipathic α-helix and binds the conserved BH3-binding groove on Bcl-2. Unlike the helical Bim or Bad BH3 motif, the C-terminal portion of the bound HBx BH3-like motif has an extended conformation and makes considerably fewer interactions with Bcl-2. These observations suggest that HBx may modulate Bcl-2 function in a way that is different from that of the classical BH3-only proteins.