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Abstract
BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and emerging data support a role of BMI1 in cancer. The central domain of BMI1 is involved in protein–protein interactions and is essential for its oncogenic activity. Here, we present the structure of BMI1 bound to the polyhomeotic protein PHC2 illustrating that the central domain of BMI1 adopts an ubiquitin-like (UBL) fold and binds PHC2 in a β-hairpin conformation. Unexpectedly, we find that the UBL domain is involved in homo-oligomerization of BMI1. We demonstrate that both the interaction of BMI1 with polyhomeotic proteins and homo-oligomerization via UBL domain are necessary for H2A ubiquitination activity of PRC1 and for clonogenic potential of U2OS cells. Here, we also emphasize need for joint application of NMR spectroscopy and X-ray crystallography to determine the overall structure of the BMI1–PHC2 complex.
Highlights
BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and emerging data support a role of BMI1 in cancer
The central domain of BMI1 has been reported to interact with the polyhomeotic PHC2 protein and we sought to characterize the molecular details of this interaction (Fig. 1a)[29,30]
BMI1 is an essential component of the canonical polycomb repressive complex 1 (PRC1) that participates in H2A ubiquitin ligase activity[26,27] and in protein–protein interactions stabilizing the overall architecture of PRC1
Summary
BMI1 is a core component of the polycomb repressive complex 1 (PRC1) and emerging data support a role of BMI1 in cancer. The central domain of BMI1 was initially predicted as a putative helix-turn-helix (HTH) domain[36] and more recently was defined as an ubiquitin-like (UBL) domain, called RAWUL (RING finger- and WD40-associated ubiquitin-like) domain[34] This domain is involved in protein–protein interactions and its best characterized binding partners are the polyhomeotic proteins (PHC1, PHC2, PHC3)[29,30]. The structure and molecular mechanisms determining how the central domain of BMI1 contributes to the overall architecture and function of the canonical PRC1 complex have not been fully elucidated To address these questions we determined the three-dimensional structure of the PHC2–BMI1 complex revealing that the BMI1 central domain adopts an ubiquitin-like (UBL) fold and binds a short, 24 amino acid fragment of PHC2 in a b-hairpin conformation. Our work reveals that both hetero- and homooligomerization of the UBL domain contribute to BMI1 function and activity
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