Structure of the AML1-ETO NHR3–PKA(RIIα) Complex and Its Contribution to AML1-ETO Activity

• Published in: Journal of molecular biology 2010-09, Vol.402 (3), p.560-577
• Main Authors: Corpora, Takeshi, Roudaia, Liya, Oo, Zaw Min, Chen, Wei, Manuylova, Ekaterina, Cai, Xiongwei, Chen, Michael J., Cierpicki, Tomasz, Speck, Nancy A., Bushweller, John H.
• Format: Article
• Language: English
• Subjects: AKAP; AML1-ETO; Animals; Binding Sites - genetics; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Cell Differentiation; Core Binding Factor Alpha 2 Subunit - chemistry; Core Binding Factor Alpha 2 Subunit - genetics; Core Binding Factor Alpha 2 Subunit - metabolism; Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit - chemistry; Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit - metabolism; Humans; leukemia; Leukemia, Myeloid, Acute - etiology; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Mice; Mutation; NHR3; Oncogene Proteins, Fusion - chemistry; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; PKA(RIIα); Protein Binding; Protein Structure, Tertiary; Proto-Oncogene Proteins - chemistry; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; RUNX1 Translocation Partner 1 Protein; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2010.08.007

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.