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The leukemia-associated AML1 (Runx1)–CBFβ complex functions as a DNA-induced molecular clamp

Nature Structural Biology volume 8, pages 371–378 (2001)Cite this article

Abstract

We have determined the structure, at 2.6 Å resolution, of the AML1 (Runx1) Runt domain–CBFβ–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-κB/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–CBFβ complex as a consequence of the human disease-associated mutations in leukemogenesis and cleidocranial dysplasia.

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Figure 1: Structure of the AML1 Runt domain–CBFβ–DNA ternary complex.
Figure 2: DNA recognition mechanism.
Figure 3: DNA-induced ordering of the 'tail' and 'wing'.
Figure 4: In vitro DNA binding assays.
Figure 5: Rel/NFκB-like DNA contacts by the Runt domain.

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Acknowledgements

We thank S. Arzt for help with data collection at ESRF beamline ID14-3; R. Williams for invaluable assistance; S.A. Islam and M.J.E. Sternberg (ICRF) for the program PREPI; J. Bushweller and H. Kanegane for sharing unpublished data; C. Müller for the preprint of his review; D. Rhodes, A. Murzin, D. Neuhaus and A. Travers for helpful discussions. A.J.W. is supported by an MRC Senior Clinical Fellowship. N.A.S. is supported by Public Health Service grants.

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Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK

    Jerónimo Bravo & Alan J. Warren

  2. Department of Biochemistry, Dartmouth Medical School, Hanover, 03755, New Hampshire, USA

    Zhe Li & Nancy A. Speck

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  1. Jerónimo Bravo
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  2. Zhe Li
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Correspondence to Alan J. Warren.

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Bravo, J., Li, Z., Speck, N. et al. The leukemia-associated AML1 (Runx1)–CBFβ complex functions as a DNA-induced molecular clamp. Nat Struct Mol Biol 8, 371–378 (2001). https://doi.org/10.1038/86264

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