Jiang Tianyu, Liu Minhao, Wu Jianping, Shi Yigong
Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Ministry of Education Key Laboratory of Protein Science, Tsinghua-Peking Joint Center for Life Sciences, Beijing Advanced Innovation Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China
Proc Natl Acad Sci U S A. 2016 Feb 23;113(8):2074-9. doi: 10.1073/pnas.1525616113. Epub 2016 Feb 8.
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.
乙肝病毒X蛋白（HBx）是一种病毒感染性和复制所必需的乙肝病毒蛋白。抗凋亡的Bcl-2家族成员被认为是HBx重要的宿主靶点之一。然而，HBx的结构和功能鲜为人知，HBx诱导致癌的分子机制仍不清楚。在本研究中，我们报道了HBx的生化和结构特征。重组HBx蛋白含有金属离子，尤其是铁和锌。HBx中一个类似BH3的基序（第110 - 135位氨基酸残基）以约193 μM的解离常数与Bcl-2结合，这比来自Bim或Bad的典型BH3基序的解离常数低得多。结构分析表明，与其他BH3基序类似，HBx的类似BH3基序采用两亲性α螺旋，并结合Bcl-2上保守的BH3结合凹槽。与螺旋状的Bim或Bad BH3基序不同，结合的HBx类似BH3基序的C末端部分具有延伸构象，与Bcl-2的相互作用显著减少。这些观察结果表明，HBx可能以不同于经典仅含BH3结构域蛋白的方式调节Bcl-2的功能。
