The leukemia-associated AML1 (Runx1)--CBF beta complex functions as a DNA-induced molecular clamp.

Abstract

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.

• Authors: J Bravo, Z Li, N A Speck, A J Warren
• Journal: Nature structural biology (Nat Struct Biol) Vol. 8 Issue 4 Pg. 371-8 (Apr 2001) ISSN: 1072-8368 [Print] United States
• PMID: 11276260 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Core Binding Factor Alpha 2 Subunit
• DNA-Binding Proteins
• NF-kappa B
• Neoplasm Proteins
• Proto-Oncogene Proteins
• RUNX1 protein, human
• Transcription Factor AP-2
• Transcription Factor RelA
• Transcription Factors
• DNA

Topics

• Amino Acid Sequence
• Amino Acid Substitution (genetics)
• Base Sequence
• Binding Sites
• Core Binding Factor Alpha 2 Subunit
• Crystallography, X-Ray
• DNA (chemistry, genetics, metabolism)
• DNA-Binding Proteins (chemistry, genetics, metabolism)
• Dimerization
• Humans
• Leukemia (metabolism)
• Models, Molecular
• Mutation (genetics)
• NF-kappa B (chemistry, metabolism)
• Neoplasm Proteins (chemistry, genetics, metabolism)
• Nucleic Acid Conformation
• Protein Binding
• Protein Structure, Tertiary
• Proto-Oncogene Proteins
• Substrate Specificity
• Transcription Factor AP-2
• Transcription Factor RelA
• Transcription Factors (chemistry, genetics, metabolism)
• Two-Hybrid System Techniques