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

JOURNAL OF MOLECULAR BIOLOGY

卷:402

Article

Corpora, Takeshi¹  Roudaia, Liya²  Oo, Zaw Min^3,4  Chen, Wei²  Manuylova, Ekaterina²  Cai, Xiongwei^3,4  Chen, Michael J.^3,4  Speck, Nancy A.^3,4  Bushweller, John H.^1,5 

[1] Univ Virginia, Dept Chem, Charlottesville, VA 22906 USA

[2] Dartmouth Med Sch, Dept Biochem, Hanover, NH 03755 USA

[3] Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19103 USA

[4] Univ Penn, Dept Cell & Dev Biol, Philadelphia, PA 19103 USA

[5] Univ Virginia, Dept Mol Physiol & Biol Phys, UVa Hlth Sci Ctr, Charlottesville, VA 22908 USA

关键词: AML1-ETO;    leukemia;    AKAP;    PKA(RII alpha);    NHR3;   

DOI  :  10.1016/j.jmb.2010.08.007

来源: Elsevier

【 摘 要 】

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(RII alpha)). We determined the solution structure of a complex between the AML1-ETO NHR3 domain and PKA(RII alpha). Based on this structure, a key residue in AML1-ETO for PKA(RII alpha) 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(RII alpha) protein interaction does not appear to significantly contribute to AML1-ETO's ability to induce leukemia. (c) 2010 Elsevier Ltd. All rights reserved.

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