title: Structural basis of CBP/p300 recruitment in leukemia induction by E2A-PBX1.
abstract: E-proteins are critical transcription factors in B-cell lymphopoiesis. E2A, 1 of 3 E-protein-encoding genes, is implicated in the induction of acute lymphoblastic leukemia through its involvement in the chromosomal translocation 1;19 and consequent expression of the E2A-PBX1 oncoprotein. An interaction involving a region within the N-terminal transcriptional activation domain of E2A-PBX1, termed the PCET motif, which has previously been implicated in E-protein silencing, and the KIX domain of the transcriptional coactivator CBP/p300, critical for leukemogenesis. However, the structural details of this interaction remain unknown. Here we report the structure of a 1:1 complex between PCET motif peptide and the KIX domain. Residues throughout the helical PCET motif that contact the KIX domain are important for both binding KIX and bone marrow immortalization by E2A-PBX1. These results provide molecular insights into E-protein-driven differentiation of B-cells and the mechanism of E-protein silencing, and reveal the PCET/KIX interaction as a therapeutic target for E2A-PBX1-induced leukemia.
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Denis
authors.forename: Seth
authors.initials: S
authors.lastname: Chitayat
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Plevin
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Patrick
authors.initials: P
authors.lastname: Thompson
authors.forename: Shuang
authors.initials: S
authors.lastname: Liu
authors.forename: Holly L
authors.initials: HL
authors.lastname: Spencer
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Ikura
authors.forename: David P
authors.initials: DP
authors.lastname: LeBrun
authors.forename: Steven P
authors.initials: SP
authors.lastname: Smith
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000737:chemistry / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D017124:Conserved Sequence; D018398:Homeodomain Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D050880:p300-CBP Transcription Factors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D015514:Oncogene Proteins, Fusion; D050880:p300-CBP Transcription Factors; C073366:TCF12 protein, human; C089847:E2A-Pbx1 fusion protein