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

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

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1
Department of Chemistry, University of Virginia, Charlottesville, VA 22906, USA.

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.

PMID:
20708017
PMCID:
PMC2945414
DOI:
10.1016/j.jmb.2010.08.007
[Indexed for MEDLINE]
Free PMC Article
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