5VTB

Crystal structure of RBBP4 bound to BCL11a peptide

Summary for 5VTB

• Entry DOI: 10.2210/pdb5vtb/pdb
• Descriptor: Histone-binding protein RBBP4, B-cell lymphoma/leukemia 11A, GLYCEROL, ... (4 entities in total)
• Functional Keywords: rbbp4, histone binding protein, wd40 domain, protein binding
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 50391.56

Authors

Meagher, J.L.,Stuckey, J.A. (deposition date: 2017-05-16, release date: 2017-12-27, Last modification date: 2023-10-04)

Primary citation

Moody, R.R.,Lo, M.C.,Meagher, J.L.,Lin, C.C.,Stevers, N.O.,Tinsley, S.L.,Jung, I.,Matvekas, A.,Stuckey, J.A.,Sun, D.
Probing the interaction between the histone methyltransferase/deacetylase subunit RBBP4/7 and the transcription factor BCL11A in epigenetic complexes.
J. Biol. Chem., 293:2125-2136, 2018

PubMed Abstract: The transcription factor BCL11A has recently been reported to be a driving force in triple-negative breast cancer (TNBC), contributing to the maintenance of a chemoresistant breast cancer stem cell (BCSC) population. Although BCL11A was shown to suppress γ-globin and p21 and to induce MDM2 expression in the hematopoietic system, its downstream targets in TNBC are still unclear. For its role in transcriptional repression, BCL11A was found to interact with several corepressor complexes; however, the mechanisms underlying these interactions remain unknown. Here, we reveal that BCL11A interacts with histone methyltransferase (PRC2) and histone deacetylase (NuRD and SIN3A) complexes through their common subunit, RBBP4/7. In fluorescence polarization assays, we show that BCL11A competes with histone H3 for binding to the negatively charged top face of RBBP4. To define that interaction, we solved the crystal structure of RBBP4 in complex with an N-terminal peptide of BCL11A (residues 2-16, BCL11A(2-16)). The crystal structure identifies novel interactions between BCL11A and the side of the β-propeller of RBBP4 that are not seen with histone H3. We next show that BCL11A(2-16) pulls down RBBP4, RBBP7, and other components of PRC2, NuRD, and SIN3A from the cell lysate of the TNBC cell line SUM149. Furthermore, we demonstrate the therapeutic potential of targeting the RBBP4-BCL11A binding by showing that a BCL11A peptide can decrease aldehyde dehydrogenase-positive BCSCs and mammosphere formation capacity in SUM149. Together, our findings have uncovered a previously unidentified mechanism that BCL11A may use to recruit epigenetic complexes to regulate transcription and promote tumorigenesis.

PubMed: 29263092
DOI: 10.1074/jbc.M117.811463

Experimental method

X-RAY DIFFRACTION (2.4 Å)