Structural basis for recognition of SMRT/N-CoR by the MYND domain and its contribution to AML1/ETO's activity.
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.
Liu
Yizhou
Y
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22906, USA.
Chen
Wei
W
Gaudet
Justin
J
Cheney
Matthew D
MD
Roudaia
Liya
L
Cierpicki
Tomasz
T
Klet
Rachel C
RC
Hartman
Kari
K
Laue
Thomas M
TM
Speck
Nancy A
NA
Bushweller
John H
JH
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*
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