Structure of the AML1-ETO NHR3-PKA(RIIα) complex and its contribution to AML1-ETO activity.
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.
Corpora
Takeshi
T
Department of Chemistry, University of Virginia, Charlottesville, VA 22906, USA.
Roudaia
Liya
L
Oo
Zaw Min
ZM
Chen
Wei
W
Manuylova
Ekaterina
E
Cai
Xiongwei
X
Chen
Michael J
MJ
Cierpicki
Tomasz
T
Speck
Nancy A
NA
Bushweller
John H
JH
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D050676:Core Binding Factor Alpha 2 Subunit / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
D050676:Core Binding Factor Alpha 2 Subunit; D054754:Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit; D015514:Oncogene Proteins, Fusion; C517819:PRKAR2A protein, human; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C082222:RUNX1T1 protein, human; D014157:Transcription Factors