Home LiteratureArticle Details
PMID: 10856244 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Structural basis for the heterodimeric interaction between the acute leukaemia-associated transcription factors AML1 and CBFbeta.

The EMBO journal ·Vol. 19 ·No. 12 ·2000-06-15 ·Pages 3004-15

Warren AJ, Bravo J, Williams RL, Rabbitts TH

Abstract

Mutations in the genes encoding the interacting proteins AML1 and CBFbeta are the most common genetic abnormalities in acute leukaemia, and congenital mutations in the related AML3 gene are associated with disorders of osteogenesis. Furthermore, the interaction of AML1 with CBFbeta is essential for haematopoiesis. We report the 2.6 A resolution crystal structure of the complex between the AML1 Runt domain and CBFbeta, which represents a paradigm for the mode of interaction of this highly conserved family of transcription factors. The structure demonstrates that point mutations associated with cleidocranial dysplasia map to the conserved heterodimer interface, suggesting a role for CBFbeta in osteogenesis, and reveals a potential protein interaction platform composed of conserved negatively charged residues on the surface of CBFbeta.

MeSH Terms
Acute Disease Amino Acid Sequence Conserved Sequence Core Binding Factor Alpha 2 Subunit Crystallography DNA-Binding Proteins/chemistry,genetics,metabolism Dimerization Drosophila Proteins Humans Leukemia Models, Molecular Molecular Sequence Data Neoplasm Proteins/chemistry,genetics,metabolism Nuclear Proteins Peptide Fragments/chemistry Protein Binding Proto-Oncogene Proteins Recombinant Proteins/chemistry,metabolism Sequence Homology, Amino Acid Static Electricity Surface Properties Transcription Factor AP-2 Transcription Factors/chemistry,genetics,metabolism Translocation, Genetic
Chemicals
Core Binding Factor Alpha 2 Subunit DNA-Binding Proteins Drosophila Proteins Neoplasm Proteins Nuclear Proteins Peptide Fragments Proto-Oncogene Proteins RUNX1 protein, human Recombinant Proteins Transcription Factor AP-2 Transcription Factors run protein, Drosophila
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Warren A J
MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 2QH, UK. [email protected]
Bravo J
Williams R L
Rabbitts T H
References (48)
48 references, click to expand
  1. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2alphaB gene associated with myeloblastic leukemias.
    Blood. 1999 Mar 15;93(6):1817-24 PMID: 10068652
  2. Automated MAD and MIR structure solution.
    Acta Crystallogr D Biol Crystallogr. 1999 Apr;55(Pt 4):849-61 PMID: 10089316
  3. Differential interactions between Brother proteins and Runt domain proteins in the Drosophila embryo and eye.
    Development. 1999 Aug;126(15):3313-22 PMID: 10393111
  4. Immunoglobulin motif DNA recognition and heterodimerization of the PEBP2/CBF Runt domain.
    Nat Struct Biol. 1999 Jul;6(7):615-9 PMID: 10404214
  5. Molecular insights into PEBP2/CBF beta-SMMHC associated acute leukemia revealed from the structure of PEBP2/CBF beta.
    Nat Struct Biol. 1999 Jul;6(7):620-3 PMID: 10404215
  6. Solution structure of core binding factor beta and map of the CBF alpha binding site.
    Nat Struct Biol. 1999 Jul;6(7):624-7 PMID: 10404216
  7. Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia.
    Nat Genet. 1999 Oct;23(2):166-75 PMID: 10508512
  8. Mutation analysis of core binding factor A1 in patients with cleidocranial dysplasia.
    Am J Hum Genet. 1999 Nov;65(5):1268-78 PMID: 10521292
  9. The Ig fold of the core binding factor alpha Runt domain is a member of a family of structurally and functionally related Ig-fold DNA-binding domains.
    Structure. 1999 Oct 15;7(10):1247-56 PMID: 10545320
  10. CBFA1 mutation analysis and functional correlation with phenotypic variability in cleidocranial dysplasia.
    Hum Mol Genet. 1999 Nov;8(12):2311-6 PMID: 10545612
  11. Molecular basis of tissue-specific gene expression mediated by the runt domain transcription factor PEBP2/CBF.
    Genes Cells. 1999 Dec;4(12):685-96 PMID: 10620014
  12. The CCP4 suite: programs for protein crystallography.
    Acta Crystallogr D Biol Crystallogr. 1994 Sep 1;50(Pt 5):760-3 PMID: 15299374
  13. t(8;21) breakpoints on chromosome 21 in acute myeloid leukemia are clustered within a limited region of a single gene, AML1.
    Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10431-4 PMID: 1720541
  14. Protein folding and association: insights from the interfacial and thermodynamic properties of hydrocarbons.
    Proteins. 1991;11(4):281-96 PMID: 1758883
  15. Oncogenic conversion of transcription factors by chromosomal translocations.
    Cell. 1991 Aug 23;66(4):619-22 PMID: 1878967
  16. Translocations, master genes, and differences between the origins of acute and chronic leukemias.
    Cell. 1991 Nov 15;67(4):641-4 PMID: 1934065
  17. Improved methods for building protein models in electron density maps and the location of errors in these models.
    Acta Crystallogr A. 1991 Mar 1;47 ( Pt 2):110-9 PMID: 2025413
  18. Purification of a mouse nuclear factor that binds to both the A and B cores of the polyomavirus enhancer.
    J Virol. 1990 Oct;64(10):4808-19 PMID: 2168969
  19. Selenomethionyl proteins produced for analysis by multiwavelength anomalous diffraction (MAD): a vehicle for direct determination of three-dimensional structure.
    EMBO J. 1990 May;9(5):1665-72 PMID: 2184035
  20. Processing of X-ray diffraction data collected in oscillation mode.
    Methods Enzymol. 1997;276:307-26 PMID: 27754618
  21. Differential protein binding in lymphocytes to a sequence in the enhancer of the mouse retrovirus SL3-3.
    Mol Cell Biol. 1988 Apr;8(4):1625-37 PMID: 2837650
  22. Functional domains of the t(8;21) fusion protein, AML-1/ETO.
    Oncogene. 1995 Nov 2;11(9):1761-9 PMID: 7478604
  23. Structure of NF-kappa B p50 homodimer bound to a kappa B site.
    Nature. 1995 Jan 26;373(6512):303-10 PMID: 7530332
  24. SCOP: a structural classification of proteins database for the investigation of sequences and structures.
    J Mol Biol. 1995 Apr 7;247(4):536-40 PMID: 7723011
  25. The immunoglobulin fold. Structural classification, sequence patterns and common core.
    J Mol Biol. 1994 Sep 30;242(4):309-20 PMID: 7932691
  26. Chromosomal translocations in human cancer.
    Nature. 1994 Nov 10;372(6502):143-9 PMID: 7969446
  27. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice.
    Nucleic Acids Res. 1994 Nov 11;22(22):4673-80 PMID: 7984417
  28. PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene.
    Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6859-63 PMID: 8341710
  29. Fusion between transcription factor CBF beta/PEBP2 beta and a myosin heavy chain in acute myeloid leukemia.
    Science. 1993 Aug 20;261(5124):1041-4 PMID: 8351518
  30. Molecular cloning and characterization of PEBP2 beta, the heterodimeric partner of a novel Drosophila runt-related DNA binding protein PEBP2 alpha.
    Virology. 1993 May;194(1):314-31 PMID: 8386878
  31. Sequence specificity of the core-binding factor.
    J Virol. 1993 Apr;67(4):2408-11 PMID: 8445737
  32. Drosophila homologs of the proto-oncogene product PEBP2/CBF beta regulate the DNA-binding properties of Runt.
    Mol Cell Biol. 1996 Mar;16(3):932-42 PMID: 8622696
  33. Over-production of proteins in Escherichia coli: mutant hosts that allow synthesis of some membrane proteins and globular proteins at high levels.
    J Mol Biol. 1996 Jul 19;260(3):289-98 PMID: 8757792
  34. Biochemical and biophysical properties of the core-binding factor alpha2 (AML1) DNA-binding domain.
    J Biol Chem. 1996 Oct 18;271(42):26251-60 PMID: 8824275
  35. The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo.
    Cell. 1996 Nov 15;87(4):697-708 PMID: 8929538
  36. Functional dissection of the alpha and beta subunits of transcription factor PEBP2 and the redox susceptibility of its DNA binding activity.
    J Biol Chem. 1996 Dec 20;271(51):33074-82 PMID: 8955155
  37. A simple screening for mutant DNA binding proteins: application to murine transcription factor PEBP2alpha subunit, a founding member of the Runt domain protein family.
    Gene. 1997 Jan 31;185(1):111-7 PMID: 9034321
  38. Treatment of multiwavelength anomalous diffraction data as a special case of multiple isomorphous replacement.
    Methods Enzymol. 1997;276:538-57 PMID: 9048381
  39. Redox regulation of the DNA binding activity in transcription factor PEBP2. The roles of two conserved cysteine residues.
    J Biol Chem. 1997 Jun 6;272(23):14497-500 PMID: 9169404
  40. The missing bone.
    Cell. 1997 May 30;89(5):677-80 PMID: 9182754
  41. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts.
    Cell. 1997 May 30;89(5):755-64 PMID: 9182763
  42. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development.
    Cell. 1997 May 30;89(5):765-71 PMID: 9182764
  43. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia.
    Cell. 1997 May 30;89(5):773-9 PMID: 9182765
  44. Missense mutations abolishing DNA binding of the osteoblast-specific transcription factor OSF2/CBFA1 in cleidocranial dysplasia.
    Nat Genet. 1997 Jul;16(3):307-10 PMID: 9207800
  45. Oncogenic transcription factors in the human acute leukemias.
    Science. 1997 Nov 7;278(5340):1059-64 PMID: 9353180
  46. Multiple functional domains of AML1: PU.1 and C/EBPalpha synergize with different regions of AML1.
    Mol Cell Biol. 1998 Jul;18(7):3915-25 PMID: 9632776
  47. Three-dimensional structure of the Stat3beta homodimer bound to DNA.
    Nature. 1998 Jul 9;394(6689):145-51 PMID: 9671298
  48. Crystallography & NMR system: A new software suite for macromolecular structure determination.
    Acta Crystallogr D Biol Crystallogr. 1998 Sep 1;54(Pt 5):905-21 PMID: 9757107
Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
DOI
10.1093/emboj/19.12.3004
Email
[email protected]
Published
2000-06-15
Pages
3004-15
Language
English
Region
England
NLM ID
8208664
PMCID
PMC203359
Subset
IM
Grants
Medical Research Council · MC_U105184308 · United Kingdom
External Links
PubMed source DOI: 10.1093/emboj/19.12.3004 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2