Structure of the AML1-ETO NHR3-PKA(RIIα) complex and its contribution to AML1-ETO activity

J Mol Biol. 2010 Sep 24;402(3):560-77. doi: 10.1016/j.jmb.2010.08.007. Epub 2010 Aug 11.

Abstract

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.

MeSH terms

  • 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, Myeloid, Acute / etiology
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Mice
  • Mutation
  • Oncogene Proteins, Fusion / chemistry*
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism
  • 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

Substances

  • Core Binding Factor Alpha 2 Subunit
  • Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit
  • Oncogene Proteins, Fusion
  • PRKAR2A protein, human
  • Proto-Oncogene Proteins
  • RUNX1 Translocation Partner 1 Protein
  • RUNX1T1 protein, human
  • Transcription Factors

Associated data

  • PDB/2KYG