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PMID:19187761

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Citation

Southall, SM, Wong, PS, Odho, Z, Roe, SM and Wilson, JR (2009) Structural basis for the requirement of additional factors for MLL1 SET domain activity and recognition of epigenetic marks. Mol. Cell 33:181-91

Abstract

The mixed-lineage leukemia protein MLL1 is a transcriptional regulator with an essential role in early development and hematopoiesis. The biological function of MLL1 is mediated by the histone H3K4 methyltransferase activity of the carboxyl-terminal SET domain. We have determined the crystal structure of the MLL1 SET domain in complex with cofactor product AdoHcy and a histone H3 peptide. This structure indicates that, in order to form a well-ordered active site, a highly variable but essential component of the SET domain must be repositioned. To test this idea, we compared the effect of the addition of MLL complex members on methyltransferase activity and show that both RbBP5 and Ash2L but not Wdr5 stimulate activity. Additionally, we have determined the effect of posttranslational modifications on histone H3 residues downstream and upstream from the target lysine and provide a structural explanation for why H3T3 phosphorylation and H3K9 acetylation regulate activity.

Links

PubMed Online version:10.1016/j.molcel.2008.12.029

Keywords

Acetylation; Amino Acid Sequence; Binding Sites; Catalytic Domain; Crystallography, X-Ray; Epigenesis, Genetic/physiology; Histone-Lysine N-Methyltransferase; Histones/chemistry; Histones/metabolism; Humans; Lysine/genetics; Lysine/metabolism; Molecular Sequence Data; Myeloid-Lymphoid Leukemia Protein/chemistry; Myeloid-Lymphoid Leukemia Protein/metabolism; Peptides/chemistry; Peptides/metabolism; Phosphorylation; Protein Conformation; Protein Methyltransferases/metabolism; Protein Structure, Tertiary; Substrate Specificity

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:KMT2A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9UBL3

F

Seeded From UniProt

complete

HUMAN:KMT2A

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15291

F

Seeded From UniProt

complete

HUMAN:RBBP5

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q03164

F

Seeded From UniProt

complete

HUMAN:ASH2L

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q03164

F

Seeded From UniProt

complete

HUMAN:KMT2A

enables

GO:0070577: lysine-acetylated histone binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KMT2A

enables

GO:0042800: histone methyltransferase activity (H3-K4 specific)

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KMT2A

enables

GO:0008270: zinc ion binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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