Hepatitis B virus X protein (HBx) plays a crucial role in the development of hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV) infection. The full-length HBx protein interacts with Bcl-x_L and is involved in the HBV replication and cell death processes. The three hydrophobic residues Trp120, Leu123, and Ile127 of the HBx BH3-like motif are essential for the Bcl-x_L-binding. On the other hand, various lengths of C-terminal-truncated HBx mutants are frequently detected in HCC tissues, and these mutants, rather than the full-length HBx, appear to be responsible for HCC development. Notably, the region spanning residues 1–120 of HBx [HBx(1 and 120)] has been strongly associated with an increased risk of HCC development. However, the mode of interaction between HBx(1–120) and Bcl-x_L remains unclear. HBx(1–120) possesses only Trp120 among the three hydrophobic residues essential for the Bcl-x_L-binding. To elucidate this interaction mode, we employed a C-terminal-deleted HBx BH3-like motif peptide composed of residues 101–120. Here, we present the NMR complex structure of Bcl-x_L and HBx(101–120). Our results demonstrate that HBx(101–120) binds to Bcl-x_L in a weaker manner. Considering the high expression of Bcl-x_L in HCC cells, this weak interaction, in conjunction with the overexpression of Bcl-x_L in HCC cells, may potentially contribute to HCC development through the interaction between C-terminal-truncated HBx and Bcl-x_L.

中文翻译：

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乙型肝炎病毒 X 蛋白 C 端缺失 BH3 样基序肽与 Bcl-xL 之间相互作用的结构见解

乙型肝炎病毒X蛋白（HBx）在与乙型肝炎病毒（HBV）感染相关的肝细胞癌（HCC）的发展中起着至关重要的作用。全长 HBx 蛋白与 Bcl-x _L相互作用，参与 HBV 复制和细胞死亡过程。_{HBx BH3 样基序的三个疏水残基 Trp120、Leu123 和 Ile127 对于 Bcl-x L}结合至关重要。另一方面，在 HCC 组织中经常检测到各种长度的 C 端截短的 HBx 突变体，这些突变体（而不是全长 HBx）似乎负责 HCC 的发展。值得注意的是，跨越 HBx 残基 1-120 的区域 [HBx(1 和 120)] 与 HCC 发展风险增加密切相关。_{然而，HBx(1-120) 和 Bcl-x L}之间的相互作用模式仍不清楚。HBx(1–120) 在 Bcl-x _L结合所必需的三个疏水残基中仅具有 Trp120。为了阐明这种相互作用模式，我们采用了由残基 101-120 组成的 C 端缺失的 HBx BH3 样基序肽。_{在这里，我们展示了 Bcl-x L}和 HBx(101–120)的 NMR 复合结构。我们的结果表明 HBx(101–120)以较弱的方式与 Bcl-x _{L结合。考虑到 HCC 细胞中 Bcl-x L}的高表达，这种弱相互作用与 HCC 细胞中 Bcl-x _L的过度表达相结合，可能通过 C 端截短的 HBx 和 Bcl- 之间的相互作用促进 HCC 的发展。 x _L。