A proline repeat domain in the Notch co-activator MAML1 is important for the p300-mediated acetylation of MAML1.
Ligand activation of Notch leads to the release of Notch IC (the intracellular receptor domain), which translocates to the nucleus and interacts with the DNA-binding protein CSL to control expression of specific target genes. In addition to ligand-mediated activation, Notch signalling can be further modulated by interactions of Notch IC with a number of other proteins. MAML1 has previously been shown to act co-operatively with the histone acetyltransferase p300 in Notch IC-mediated transcription. In the present study we show that the N-terminal domain of MAML1 directly interacts with both p300 and histones, and the p300-MAML1 complex specifically acetylates histone H3 and H4 tails in chromatin. Furthermore, p300 acetylates MAML1 and evolutionarily conserved lysine residues in the MAML1 N-terminus are direct substrates for p300-mediated acetylation. The N-terminal domain of MAML1 contains a proline repeat motif (PXPAAPAP) that was previously shown to be present in p53 and important for the p300-p53 interaction. We show that the MAML1 proline repeat motif interacts with p300 and enhances the activity of the MAML1 N-terminus in vivo. These findings suggest that the N-terminal domain of MAML1 plays an important role in Notch-regulated transcription, by direct interactions with Notch, p300 and histones.
Saint Just Ribeiro
Mariana
M
Department of Biosciences and Nutrition, Karolinska Institutet, 141 86 Stockholm, Sweden.
Hansson
Magnus L
ML
Wallberg
Annika E
AE
D000107:Acetylation; D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011392:Proline / Q000737:chemistry*; D051880:Receptors, Notch / Q000378:metabolism*; D018411:Spodoptera; D015534:Trans-Activators; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors / Q000378:metabolism*
D002843:Chromatin; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D006657:Histones; C430872:MAML1 protein, human; D009687:Nuclear Proteins; D051880:Receptors, Notch; D015534:Trans-Activators; D014157:Transcription Factors; D011392:Proline; D050880:p300-CBP Transcription Factors; D008239:Lysine