Bivalent interaction of the PZP domain of BRPF1 with the nucleosome impacts chromatin dynamics and acetylation

• Published in: Nucleic acids research Vol. 44; no. 1; pp. 472 - 484
• Main Authors: Klein, Brianna J., Muthurajan, Uma M., Lalonde, Marie-Eve, Gibson, Matthew D., Andrews, Forest H., Hepler, Maggie, Machida, Shinichi, Yan, Kezhi, Kurumizaka, Hitoshi, Poirier, Michael G., Côté, Jacques, Luger, Karolin, Kutateladze, Tatiana G.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 08.01.2016
• Subjects: Acetylation; Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Amino Acid Sequence; Chromatin - genetics; Chromatin - metabolism; DNA - chemistry; DNA - metabolism; Histones - metabolism; Humans; Models, Molecular; Molecular Sequence Data; Multiprotein Complexes; Nuclear Proteins - chemistry; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Nucleosomes - genetics; Nucleosomes - metabolism; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs; Protein Stability; Sequence Alignment; Structural Biology
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkv1321

BRPF1 (bromodomain PHD finger 1) is a core subunit of the MOZ histone acetyltransferase (HAT) complex, critical for normal developmental programs and implicated in acute leukemias. BRPF1 contains a unique assembly of zinc fingers, termed a PZP domain, the physiological role of which remains unclear. Here, we elucidate the structure-function relationship of this novel epigenetic reader and detail the biological and mechanistic consequences of its interaction with nucleosomes. PZP has a globular architecture and forms a 2:1 stoichiometry complex with the nucleosome, bivalently interacting with histone H3 and DNA. This binding impacts the nucleosome dynamics, shifting the DNA unwrapping/rewrapping equilibrium toward the unwrapped state and increasing DNA accessibility. We demonstrate that the DNA-binding function of the BRPF1 PZP domain is required for the MOZ-BRPF1-ING5-hEaf6 HAT complex to be recruited to chromatin and to acetylate nucleosomal histones. Our findings reveal a novel link between chromatin dynamics and MOZ-mediated acetylation.