7m10 | pdb_00007m10
PHF2 PHD Domain Complexed with Peptide From N-terminus of VRK1
Structural highlights
FunctionPHF2_HUMAN Lysine demethylase that demethylates both histones and non-histone proteins. Enzymatically inactive by itself, and becomes active following phosphorylation by PKA: forms a complex with ARID5B and mediates demethylation of methylated ARID5B. Demethylation of ARID5B leads to target the PHF2-ARID5B complex to target promoters, where PHF2 mediates demethylation of dimethylated 'Lys-9' of histone H3 (H3K9me2), followed by transcription activation of target genes. The PHF2-ARID5B complex acts as a coactivator of HNF4A in liver. PHF2 is recruited to trimethylated 'Lys-4' of histone H3 (H3K4me3) at rDNA promoters and promotes expression of rDNA.[1] [2] [3] Publication Abstract from PubMedThe reader ability of PHD fingers is largely limited to the recognition of the histone H3 N-terminal tail. Distinct subsets of PHDs bind either H3K4me3 (a transcriptional activator mark) or H3K4me0 (a transcriptional repressor state). Structural studies have identified common features among the different H3K4me3 effector PHDs, including (1) removal of the initiator methionine residue of H3 to prevent steric interference, (2) a groove where arginine-2 binds, and (3) an aromatic cage that engages methylated lysine-4. We hypothesize that some PHDs might have the ability to engage with non-histone ligands, as long as they adhere to these three rules. A search of the human proteome revealed an enrichment of chromatin-binding proteins that met these criteria, which we termed H3 N-terminal mimicry proteins (H3TMs). Seven H3TMs were selected, and used to screen a protein domain microarray for potential effector domains, and they all had the ability to bind H3K4me3-interacting effector domains. Furthermore, the binding affinity between the VRK1 peptide and the PHD domain of PHF2 is approximately 3-fold stronger than that of PHF2 and H3K4me3 interaction. The crystal structure of PHF2 PHD finger bound with VRK1 K4me3 peptide provides a molecular basis for stronger binding of VRK1 peptide. In addition, a number of the H3TMs peptides, in their unmethylated form, interact with NuRD transcriptional repressor complex. Our findings provide in vitro evidence that methylation of H3TMs can promote interactions with PHD and Tudor domain-containing proteins and potentially block interactions with the NuRD complex. We propose that these interactions can occur in vivo as well. Histone H3 N-terminal mimicry drives a novel network of methyl-effector interactions.,Chen J, Horton J, Sagum C, Zhou J, Cheng X, Bedford MT Biochem J. 2021 May 28;478(10):1943-1958. doi: 10.1042/BCJ20210203. PMID:33969871[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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