title: Structure and site-specific recognition of histone H3 by the PHD finger of human autoimmune regulator.
abstract: Human autoimmune regulator (AIRE) functions to control thymic expression of tissue-specific antigens via sequence-specific histone H3 recognition by its plant homeodomain (PHD) finger. Mutations in the AIRE PHD finger have been linked to autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Here we report the three-dimensional solution structure of the first PHD finger of human AIRE bound to a histone H3 peptide. The structure reveals a detailed network of interactions between the protein and the amino-terminal residues of histone H3, and particularly key electrostatic interactions of a conserved aspartic acid 297 in AIRE with the unmodified lysine 4 of histone H3 (H3K4). NMR binding study with H3 peptides carrying known posttranslational modifications flanking H3K4 confirms that transcriptional regulation by AIRE through its interactions with histone H3 is confined to the first N-terminal eight residues in H3. Our study offers a molecular explanation for the APECED mutations and helps define a subclass of the PHD finger family proteins that recognize histone H3 in a sequence-specific manner.
authors.affiliation: Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York University, One Gustave L Levy Place, New York, NY 10029, USA.
authors.forename: Suvobrata
authors.initials: S
authors.lastname: Chakravarty
authors.forename: Lei
authors.initials: L
authors.lastname: Zeng
authors.forename: Ming-Ming
authors.initials: MM
authors.lastname: Zhou
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D044127:Epigenesis, Genetic; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014157:Transcription Factors / Q000737:chemistry* / Q000378:metabolism; D000096927:AIRE Protein
chemical_list: D006657:Histones; D010455:Peptides; D014157:Transcription Factors; D000096927:AIRE Protein