title: The acute myeloid leukemia fusion protein AML1-ETO targets E proteins via a paired amphipathic helix-like TBP-associated factor homology domain.
abstract: Up to 15% of acute myeloid leukemias (AMLs) are characterized by the abnormal expression of the eight-twenty-one (ETO) transcriptional corepressor within an AML1-ETO fusion protein. The t(8;21) chromosomal translocation serves not only to disrupt WT AML1 function but also to introduce ETO activity during hematopoiesis. AML1-ETO was recently shown to inhibit E protein transactivation by physically displacing WT coactivator proteins in an interaction mediated by ETO. Here, we present the 3D solution structure of the human ETO TAFH (eTAFH) domain implicated in AML1-ETO:E protein interactions and report an unexpected fold similarity to paired amphipathic helix domains from the transcriptional corepressor Sin3. We identify and characterize a conserved surface on eTAFH that is essential for ETO:E protein recognition and show that the mutation of key conserved residues at this site alleviates ETO-based silencing of E protein transactivation. Our results address uncharacterized aspects of the corepression mechanism of ETO and suggest that eTAFH may serve to recruit ETO (or AML1-ETO) to DNA-bound transcription factors. Together, these findings imply that a cofactor exchange mechanism, analogous to that described for E protein inhibition, may represent a common mode of action for ETO.
authors.affiliation: *Division of Signaling Biology, Ontario Cancer Institute, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto Medical Discovery Tower, 101 College Street, Toronto, ON, Canada M5G 1L7.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Plevin
authors.affiliation: Department of Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, OH 45267-0521; and.|Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10021.
authors.forename: Jinsong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, 3125 Eden Avenue, Cincinnati, OH 45267-0521; and.
authors.forename: Chun
authors.initials: C
authors.lastname: Guo
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10021 roeder@mail.rockefeller.edu mikura@uhnres.utoronto.ca.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Roeder
authors.affiliation: *Division of Signaling Biology, Ontario Cancer Institute, University Health Network, and Department of Medical Biophysics, University of Toronto, Toronto Medical Discovery Tower, 101 College Street, Toronto, ON, Canada M5G 1L7; roeder@mail.rockefeller.edu mikura@uhnres.utoronto.ca.
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Ikura
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D050676:Core Binding Factor Alpha 2 Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D000075142:RUNX1 Translocation Partner 1 Protein; D040681:Structural Homology, Protein; D035381:TATA-Binding Protein Associated Factors / Q000737:chemistry*
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D035381:TATA-Binding Protein Associated Factors