2h7b
Solution structure of the eTAFH domain from the human leukemia-associated fusion protein AML1-ETO
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OverviewOverview
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.
About this StructureAbout this Structure
2H7B is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
The acute myeloid leukemia fusion protein AML1-ETO targets E proteins via a paired amphipathic helix-like TBP-associated factor homology domain., Plevin MJ, Zhang J, Guo C, Roeder RG, Ikura M, Proc Natl Acad Sci U S A. 2006 Jul 5;103(27):10242-7. Epub 2006 Jun 27. PMID:16803958
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