AML1-ETO 复合物的 NHR3-PKA(RIIα)结构及其对 AML1-ETO 活性的贡献。
Structure of the AML1-ETO NHR3-PKA(RIIα) complex and its contribution to AML1-ETO activity.
机构信息
Department of Chemistry, University of Virginia, Charlottesville, VA 22906, USA.
出版信息
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.
摘要
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 部分包含 nervy 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(RIIα))的调节亚基相互作用。我们确定了 AML1-ETO NHR3 结构域与 PKA(RIIα)之间复合物的溶液结构。基于该结构，对 AML1-ETO 中与 PKA(RIIα)结合的关键残基进行了突变。该突变并未破坏 AML1-ETO 增强原代小鼠骨髓细胞集落形成能力或抑制增殖或粒细胞分化的能力。将该突变引入 AML1-ETO 对体内白血病发生的影响很小。因此，NHR3-PKA(RIIα)蛋白相互作用似乎并未显著促进 AML1-ETO 诱导白血病的能力。
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