Structure of the AML1-ETO eTAFH domain-HEB peptide complex and its contribution to AML1-ETO activity.
AML1-ETO is the chimeric protein product of the t(8;21) in acute myeloid leukemia. The ETO portion of the fusion protein includes the eTAFH domain, which is homologous to several TATA binding protein-associated factors (TAFs) and interacts with E proteins (E2A and HEB). It has been proposed that AML1-ETO-mediated silencing of E protein function might be important for t(8;21) leukemogenesis. Here, we determined the solution structure of a complex between the AML1-ETO eTAFH domain and an interacting peptide from HEB. On the basis of the structure, key residues in AML1-ETO for HEB association were mutated. These mutations do not impair the ability of AML1-ETO to enhance the clonogenic capacity of primary mouse bone marrow cells and do not eliminate its ability to repress proliferation or granulocyte differentiation. Therefore, the eTAFH-E protein interaction appears to contribute relatively little to the activity of AML1-ETO.
Park
Sangho
S
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
Chen
Wei
W
Cierpicki
Tomasz
T
Tonelli
Marco
M
Cai
Xiongwei
X
Speck
Nancy A
NA
Bushweller
John H
JH
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D019556:COS Cells; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D050676:Core Binding Factor Alpha 2 Subunit / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006098:Granulocytes / Q000166:cytology / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019906:Nuclear Magnetic Resonance, Biomolecular; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D050800:STAT6 Transcription Factor; D014157:Transcription Factors; C493598:MTG8 protein, mouse; C489428:Myc protein, mouse; C493726:Runx1 protein, mouse; C494100:Stat6 protein, mouse; C489532:Tcf12 protein, mouse