The leukemia-associated AML1 (Runx1)--CBF beta complex functions as a DNA-induced molecular clamp.
We have determined the structure, at 2.6 A resolution, of the AML1 (Runx1) Runt domain--CBF beta--DNA ternary complex, the most common target for mutations in human leukemia. The structure reveals that the Runt domain DNA binding mechanism is unique within the p53 family of transcription factors. The extended C-terminal 'tail' and 'wing' elements adopt a specific DNA-bound conformation that clamps the phosphate backbone between the major and minor grooves of the distorted B-form DNA recognition site. Furthermore, the extended 'tail' mediates most of the NF-kappa B/Rel-like base-specific contacts in the major groove. The structure clearly explains the molecular basis for the loss of DNA binding function of the Runt domain--CBF beta complex as a consequence of the human disease-associated mutations in leukemogenesis and cleidocranial dysplasia.
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK.
J
J
Bravo
Z
Z
Li
N A
NA
Speck
A J
AJ
Warren
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D001483:Base Sequence; D001665:Binding Sites; D050676:Core Binding Factor Alpha 2 Subunit; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins; D013379:Substrate Specificity; D050656:Transcription Factor AP-2; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D050656:Transcription Factor AP-2; D051996:Transcription Factor RelA; D014157:Transcription Factors; D004247:DNA