Structure of the AML1-ETO NHR3–PKA(RIIα) Complex and Its Contribution to AML1-ETO Activity
Copyright policy )Structure of the AML1-ETO NHR3–PKA(RIIα) Complex and Its Contribution to AML1-ETO Activity
AML1-ETO is the chimeric protein product of t(8;21) in acute myeloid leukemia. The ETO portion of the fusion protein includes the nervy homology region (NHR) 3 domain, which shares homology with A-kinase anchoring proteins and interacts with the regulatory subunit of type II cAMP-dependent protein kinase A (PKA(RIIα)). We determined the solution structure of a complex between the AML1-ETO NHR3 domain and PKA(RIIα). Based on this structure, a key residue in AML1-ETO for PKA(RIIα) association was mutated. This mutation did not disrupt AML1-ETO's ability to enhance the clonogenic capacity of primary mouse bone marrow cells or its ability to repress proliferation or granulocyte differentiation. Introduction of the mutation into AML1-ETO had minimal impact on in vivo leukemogenesis. Therefore, the NHR3-PKA(RIIα) protein interaction does not appear to significantly contribute to AML1-ETO's ability to induce leukemia.
- University of Pennsylvania United States
- Dartmouth College United States
- University of Virginia United States
Binding Sites, Oncogene Proteins, Fusion, Bone Marrow Cells, Cell Differentiation, Protein Structure, Tertiary, Leukemia, Myeloid, Acute, Mice, RUNX1 Translocation Partner 1 Protein, Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit, Proto-Oncogene Proteins, Core Binding Factor Alpha 2 Subunit, Mutation, Animals, Humans, Protein Binding, Transcription Factors
Binding Sites, Oncogene Proteins, Fusion, Bone Marrow Cells, Cell Differentiation, Protein Structure, Tertiary, Leukemia, Myeloid, Acute, Mice, RUNX1 Translocation Partner 1 Protein, Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit, Proto-Oncogene Proteins, Core Binding Factor Alpha 2 Subunit, Mutation, Animals, Humans, Protein Binding, Transcription Factors
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