Structure of the AML1-ETO NHR3-KA(RIIα) Complex and Its Contribution to AML1-ETO Activity
Structure of the AML1-ETO NHR3-KA(RIIα) Complex and Its Contribution to AML1-ETO Activity
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DOI：
10.1016/j.jmb.2010.08.007
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发表时间：
2010-09-24
影响因子：
5.6
通讯作者：
Bushweller, John H.
中科院分区：
文献类型：
--
作者：
Corpora, Takeshi;Roudaia, Liya;Bushweller, John H.
AML1-ETO是急性髓系白血病中t（8;21）的嵌合蛋白产物。融合蛋白的ETO部分包括神经同源区（NHR） 3结构域，该结构域与A激酶锚定蛋白具有同源性，并与II型camp依赖性蛋白激酶A（PKA(RII α)）的调控亚基相互作用。我们确定了AML1-ETO NHR3结构域和PKA（RII α）之间的复合物的溶液结构。基于这种结构，AML1-ETO中一个与PKA（RII α）关联的关键残基发生突变。这种突变并没有破坏AML1-ETO增强小鼠原代骨髓细胞克隆生成能力的能力，也没有破坏AML1-ETO抑制增殖或粒细胞分化的能力。将突变引入AML1-ETO对体内白血病发生的影响很小。因此，NHR3-PKA（RII α）蛋白相互作用似乎并未显著促进AML1-ETO诱导白血病的能力。(c) 2010 Elsevier Ltd.版权所有。
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.