4JOL

Complex structure of AML1-ETO NHR2 domain with HEB fragment

Summary for 4JOL

• Entry DOI: 10.2210/pdb4jol/pdb
• Descriptor: Protein CBFA2T1, Transcription factor 12 (2 entities in total)
• Functional Keywords: leukemia; aml1-eto; heb; nhr2 domain, dna binding protein
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q06455 Q99081
• Total number of polymer chains: 8
• Total formula weight: 42632.38

Authors

Wang, Z.,Patel, D.J. (deposition date: 2013-03-18, release date: 2013-06-26, Last modification date: 2023-09-20)

Primary citation

Sun, X.J.,Wang, Z.,Wang, L.,Jiang, Y.,Kost, N.,Soong, T.D.,Chen, W.Y.,Tang, Z.,Nakadai, T.,Elemento, O.,Fischle, W.,Melnick, A.,Patel, D.J.,Nimer, S.D.,Roeder, R.G.
A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis.
Nature, 500:93-97, 2013

PubMed Abstract: Transcription factors are frequently altered in leukaemia through chromosomal translocation, mutation or aberrant expression. AML1-ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukaemia, is a transcription factor implicated in both gene repression and activation. AML1-ETO oligomerization, mediated by the NHR2 domain, is critical for leukaemogenesis, making it important to identify co-regulatory factors that 'read' the NHR2 oligomerization and contribute to leukaemogenesis. Here we show that, in human leukaemic cells, AML1-ETO resides in and functions through a stable AML1-ETO-containing transcription factor complex (AETFC) that contains several haematopoietic transcription (co)factors. These AETFC components stabilize the complex through multivalent interactions, provide multiple DNA-binding domains for diverse target genes, co-localize genome wide, cooperatively regulate gene expression, and contribute to leukaemogenesis. Within the AETFC complex, AML1-ETO oligomerization is required for a specific interaction between the oligomerized NHR2 domain and a novel NHR2-binding (N2B) motif in E proteins. Crystallographic analysis of the NHR2-N2B complex reveals a unique interaction pattern in which an N2B peptide makes direct contact with side chains of two NHR2 domains as a dimer, providing a novel model of how dimeric/oligomeric transcription factors create a new protein-binding interface through dimerization/oligomerization. Intriguingly, disruption of this interaction by point mutations abrogates AML1-ETO-induced haematopoietic stem/progenitor cell self-renewal and leukaemogenesis. These results reveal new mechanisms of action of AML1-ETO, and provide a potential therapeutic target in t(8;21)-positive acute myeloid leukaemia.

PubMed: 23812588
DOI: 10.1038/nature12287

Experimental method

X-RAY DIFFRACTION (2.906 Å)