Structural analysis of EPOP BC-box binding to the elongin BC complex

Abstract

The elongin BC complex (ELOBC) interacts with BC-box-containing proteins and plays a role in various cellular processes, including transcriptional regulation and ubiquitination. Elongin BC and polycomb repressive complex 2-associated protein (EPOP) contains a BC-box motif in its N-terminal region and influences cancer cell proliferation and differentiation. A previous study showed that a BC-box containing an EPOP-derived peptide suppresses cancer cell growth and induces apoptosis by disrupting the interaction between the ELOBC and its partner proteins. Here, we report the crystal structure of the EPOP BC-box peptide bound to the ELOBC and compare it with the structures of other BC-box-containing proteins in complex with the ELOBC. The overall structure of interactions between the BC-box and the ELOC was similar across different complexes, indicating a conserved binding mode. Our structural analysis revealed that the strictly conserved leucine residue (Leu40) within the BC-box of EPOP, which was previously suggested to be critical for interactions between the BC-box and the ELOC, was deeply embedded in the hydrophobic pocket of the ELOC protein. This study provided structural insights into BC-box-mediated protein-protein interactions and may serve as a fundamental resource for developing small molecules that modulate the interactions between ELOBC and BC-box-containing proteins.