6B7G

Solution NMR structure of BCoR in complex with AF9 (BCoR-AF9)

Summary for 6B7G

• Entry DOI: 10.2210/pdb6b7g/pdb
• Related: 2LM0 2MV7 2N4Q
• NMR Information: BMRB: 27271
• Descriptor: Protein AF-9, BCL-6 corepressor (2 entities in total)
• Functional Keywords: complex, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 11991.55

Authors

Schmidt, C.R.,Kuntimaddi, A.,Leach, B.I.,Bushweller, J.H. (deposition date: 2017-10-04, release date: 2018-10-10, Last modification date: 2024-05-15)

Primary citation

Schmidt, C.R.,Achille, N.J.,Kuntimaddi, A.,Boulton, A.M.,Leach, B.I.,Zhang, S.,Zeleznik-Le, N.J.,Bushweller, J.H.
BCOR Binding to MLL-AF9 Is Essential for Leukemia via Altered EYA1, SIX, and MYC Activity.
Blood Cancer Discov, 1:162-177, 2020

PubMed Abstract: MLL is a target of chromosomal translocations in acute leukemias with poor prognosis. The common MLL fusion partner AF9 (MLLT3) can directly bind to AF4, DOT1L, BCOR, and CBX8. To delineate the relevance of BCOR and CBX8 binding to MLL-AF9 for leukemogenesis, here we determine protein structures of AF9 complexes with CBX8 and BCOR, and show that binding of all four partners to AF9 is mutually exclusive. Using the structural analyses, we identify point mutations that selectively disrupt AF9 interactions with BCOR and CBX8. In bone marrow stem/progenitor cells expressing point mutant CBX8 or point mutant MLL-AF9, we show that disruption of direct CBX8/MLL-AF9 binding does not impact cell proliferation, whereas loss of direct BCOR/MLL-AF9 binding causes partial differentiation and increased proliferation. Strikingly, loss of MLL-AF9/BCOR binding abrogated its leukemogenic potential in a mouse model. The MLL-AF9 mutant deficient for BCOR binding reduces the expression of the EYA1 phosphatase and the protein level of c-Myc. Reduction in BCOR binding to MLL-AF9 alters a MYC-driven gene expression program, as well as altering expression of SIX-regulated genes, likely contributing to the observed reduction in the leukemia-initiating cell population.

PubMed: 32954361
DOI: 10.1158/2643-3230.BCD-20-0036

Experimental method

SOLUTION NMR