title: Crystal structure and functional analysis of the histone methyltransferase SET7/9.
abstract: Methylation of lysine residues in the N-terminal tails of histones is thought to represent an important component of the mechanism that regulates chromatin structure. The evolutionarily conserved SET domain occurs in most proteins known to possess histone lysine methyltransferase activity. We present here the crystal structure of a large fragment of human SET7/9 that contains a N-terminal beta-sheet domain as well as the conserved SET domain. Mutagenesis identifies two residues in the C terminus of the protein that appear essential for catalytic activity toward lysine-4 of histone H3. Furthermore, we show how the cofactor AdoMet binds to this domain and present biochemical data supporting the role of invariant residues in catalysis, binding of AdoMet, and interactions with the peptide substrate.
authors.affiliation: Structural Biology Group, National Institute for Medical Research, The Ridgeway, Mill Hill, London, United Kingdom.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Wilson
authors.forename: Chun
authors.initials: C
authors.lastname: Jing
authors.forename: Philip A
authors.initials: PA
authors.lastname: Walker
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Martin
authors.forename: Steven A
authors.initials: SA
authors.lastname: Howell
authors.forename: G Michael
authors.initials: GM
authors.lastname: Blackburn
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Gamblin
authors.forename: Bing
authors.initials: B
authors.lastname: Xiao
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002384:Catalysis; D020134:Catalytic Domain; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000737:chemistry*; D029721:Drosophila Proteins / Q000737:chemistry*; D004926:Escherichia coli / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008780:Methyltransferases; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry; D063151:Polycomb Repressive Complex 2; D011485:Protein Binding; D011487:Protein Conformation; D011496:Protein Methyltransferases; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D013379:Substrate Specificity; D014157:Transcription Factors; D014508:Urea / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D006657:Histones; D009687:Nuclear Proteins; D010455:Peptides; D012097:Repressor Proteins; D014157:Transcription Factors; C063460:Trl protein, Drosophila; D014508:Urea; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011496:Protein Methyltransferases; C083329:E(z) protein, Drosophila; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; C540312:SETD7 protein, human; D008239:Lysine