title: Structural basis for recognition of SMRT/N-CoR by the MYND domain and its contribution to AML1/ETO's activity.
abstract: AML1/ETO results from the t(8;21) associated with 12%-15% of acute myeloid leukemia. The AML1/ETO MYND domain mediates interactions with the corepressors SMRT and N-CoR and contributes to AML1/ETO's ability to repress proliferation and differentiation of primary bone marrow cells as well as to enhance their self renewal in vitro. We solved the solution structure of the MYND domain and show it to be structurally homologous to the PHD and RING finger families of proteins. We also determined the solution structure of an MYND-SMRT peptide complex. We demonstrated that a single amino acid substitution that disrupts the interaction between the MYND domain and the SMRT peptide attenuated AML1/ETO's effects on proliferation, differentiation, and gene expression.
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22906, USA.
authors.forename: Yizhou
authors.initials: Y
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Justin
authors.initials: J
authors.lastname: Gaudet
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Cheney
authors.forename: Liya
authors.initials: L
authors.lastname: Roudaia
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Klet
authors.forename: Kari
authors.initials: K
authors.lastname: Hartman
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Laue
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Speck
authors.forename: John H
authors.initials: JH
authors.lastname: Bushweller
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C107844:AML1-ETO fusion protein, human; D050676:Core Binding Factor Alpha 2 Subunit; C539127:NCOR1 protein, human; C539128:Ncor1 protein, mouse; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D012097:Repressor Proteins