BMI1 regulates PRC1 architecture and activity through homo- and hetero-oligomerization.
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.
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Felicia
F
Gray
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Hyo Je
HJ
Cho
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Shirish
S
Shukla
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Shihan
S
He
Translational Oncology Program, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA.
Ashley
A
Harris
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Bohdan
B
Boytsov
Deutsches Zentrum fur Neurodegenerative Erkrankungen (DZNE), Am Fassberg 11, 37077 Goettingen, Germany.|Max-Planck Institute of Biophysical Chemistry, NMR-based Department for Structural Biology, Am Fassberg 11, 37077 Goettingen, Germany.
Łukasz
Ł
Jaremko
Max-Planck Institute of Biophysical Chemistry, NMR-based Department for Structural Biology, Am Fassberg 11, 37077 Goettingen, Germany.
Mariusz
M
Jaremko
Department of Biochemistry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, USA.
Borries
B
Demeler
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.|Translational Oncology Program, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48109, USA.
Elizabeth R
ER
Lawlor
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Jolanta
J
Grembecka
Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
Tomasz
T
Cierpicki
D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D063150:Polycomb Repressive Complex 1 / Q000737:chemistry / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D000072417:Protein Domains; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D054875:Ubiquitination
C069077:BMI1 protein, human; D006657:Histones; C485977:PHC2 protein, human; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1