2H7B

Solution structure of the eTAFH domain from the human leukemia-associated fusion protein AML1-ETO

Summary for 2H7B

• Entry DOI: 10.2210/pdb2h7b/pdb
• NMR Information: BMRB: 7147
• Descriptor: Core-binding factor, ML1-ETO (1 entity in total)
• Functional Keywords: 4 helix bundle, transcription
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 11887.72

Authors

Plevin, M.J.,Zhang, J.,Guo, C.,Roeder, R.G.,Ikura, M. (deposition date: 2006-06-01, release date: 2006-07-11, Last modification date: 2024-05-29)

Primary citation

Plevin, M.J.,Zhang, J.,Guo, C.,Roeder, R.G.,Ikura, M.
The acute myeloid leukemia fusion protein AML1-ETO targets E proteins via a paired amphipathic helix-like TBP-associated factor homology domain
Proc.Natl.Acad.Sci.USA, 103:10242-10247, 2006

PubMed Abstract: 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.

PubMed: 16803958
DOI: 10.1073/pnas.0603463103

Experimental method

SOLUTION NMR