Structural Basis of Plant Homeodomain Finger 6 (PHF6) Recognition by Retinoblastoma Binding Protein 4 (RBBP4) Component of the Nucleosome Remodeling and Deacetylase (NuRD) Complex [Gene Regulation]

January 19th, 2015 by Liu, Z., Li, F., Zhang, B., Li, S., Wu, J., Shi, Y.

The Nucleosome Remodeling and Deacetylase (NuRD) complex is a conserved transcriptional coregulator that contains both chromatin remodeling and histone deacetylase activities. Mutations of plant homeodomain finger 6 (PHF6) are found in patients with Borjeson-Forssman-Lehmann syndrome (BFLS), T-cell acute lymphoblastic leukemia (T-ALL), or acute myeloid leukemia (AML). Recently, PHF6 was identified to interact with the NuRD complex, and that interaction is mediated by RBBP4 component. However, little is known about the molecular basis for the interaction. Here, we present the crystal structure of the complex, NuRD subunit RBBP4 bound to the PHF6 peptide (residues 162-170). The PHF6 peptide binds to the top surface of the RBBP4 β-propeller. A pair of positively charged residues of PHF6 peptide insert into the negatively charged pocket of RBBP4, which is critical for the interaction between PHF6 and RBBP4. Corresponding PHF6 mutants impair this interaction in vitro and in vivo. Structural comparison shows that the PHF6-binding pocket overlaps with FOG1 and histone H3 on RBBP4/Nurf55, but it is distinct from the pocket recognizing histone H4, Su(z)12 and MTA1. We further show that the middle disordered region (residues 145-207, containing the RBBP4-binding motif) is sufficient for the transcriptional repression mediated by PHF6 on GAL4 reporter, and knockdown of RBBP4 diminished the PHF6-mediated repression. Our PHF6-RBBP4 complex structure provides insights into the molecular basis of PHF6-NuRD complex interaction and implicates a role for PHF6 in chromatin structure modulation and gene regulation.
  • Posted in Journal of Biological Chemistry, Publications
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