Submitted June 3, 2008
Accepted January 18, 2009
Structure of the AML1-ETO eTAFH domain - HEB peptide complex and its contribution to AML1-ETO activity
Sangho Park, Wei Chen, Tomasz Cierpicki, Marco Tonelli, Xiongwei Cai, Nancy A. Speck, and John H. Bushweller*
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, United States
Department of Biochemistry, Dartmouth Medical School, Hanover, NH, United States
National Magnetic Resonance Facility at Madison, Biochemistry Department, University of Wisconsin-Madison, Madison, WI, United States
Abramson Family Cancer Research Institute and Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, United States
Department of Chemistry, University of Virginia, Charlottesville, VA, United States
* Corresponding author; email: jhb4v{at}virginia.edu.
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. Based on the structure, key residues in AML1-ETO for HEB association were mutated. These mutations do not impair AML1-ETO's ability 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 AML1-ETO's activity.
