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-xL 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-xL-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-xL remains unclear. HBx(1–120) possesses only Trp120
among the three hydrophobic residues essential for the Bcl-xL-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-xL and HBx(101–120).
Our results demonstrate that HBx(101–120) binds to Bcl-xL in a weaker manner. Considering the high expression of Bcl-xL in HCC cells, this weak interaction, in conjunction with
the overexpression of Bcl-xL in HCC cells, may potentially
contribute to HCC development through the interaction between C-terminal-truncated
HBx and Bcl-xL.