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PMID: 8600458 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Hox homeodomain proteins exhibit selective complex stabilities with Pbx and DNA.

Nucleic acids research ·Vol. 24 ·No. 5 ·1996-03-01 ·Pages 898-906

Shen WF, Chang CP, Rozenfeld S, Sauvageau G, Humphries RK, Lu M, Lawrence HJ, Cleary ML, Largman C

Abstract

Eight of the nine homeobox genes of the Hoxb locus encode proteins which contain a conserved hexapeptide motif upstream from the homeodomain. All eight proteins (Hoxb-1-Hoxb-8) bind to a target oligonucleotide in the presence of Pbx1a under conditions where minimal or no binding is detected for the Hox or Pbx1a proteins alone. The stabilities of the Hox-Pbx1a-DNA complexes vary >100-fold, with the proteins from the middle of the locus (Hoxb-5 and Hoxb-6) forming very stable complexes, while Hoxb-4, Hoxb-7 and Hoxb-8 form complexes of intermediate stability and proteins at the 3'-side of the locus (Hoxb-1-Hoxb-3) form complexes which are very unstable. Although Hox-b proteins containing longer linker sequences between the hexapeptide and homeodomains formed unstable complexes, shortening the linker did not confer complex stability. Homeodomain swapping experiments revealed that this motif does not independently determine complex stability. Naturally occurring variations within the hexapeptides of specific Hox proteins also do not explain complex stability differences. However, two core amino acids (tryptophan and methionine) which are absolutely conserved within the hexapeptide domains appear to be required for complex formation. Removal of N- and C-terminal flanking regions did not influence complex stability and the members of paralog group 4 (Hoxa-4, b-4, c-4 and d-4), which share highly conserved hexapeptides, linkers and homeodomains but different flanking regions, form complexes of similar stability. These data suggest that the structural features of Hox proteins which determine Hox-Pbx1a-DNA complex stability reside within the precise structural relationships between the homeodomain, hexapeptide and linker regions.

MeSH Terms
Amino Acid Sequence Base Sequence DNA/metabolism DNA-Binding Proteins/metabolism Homeodomain Proteins/metabolism Macromolecular Substances Molecular Sequence Data Pre-B-Cell Leukemia Transcription Factor 1 Protein Binding Proto-Oncogene Proteins/metabolism Sequence Analysis
Chemicals
DNA-Binding Proteins Homeodomain Proteins Macromolecular Substances Pre-B-Cell Leukemia Transcription Factor 1 Proto-Oncogene Proteins pbx1 protein, human DNA
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Shen W F
Department of Medicine San Francisco Veterans Affairs Medical Center, CA 94121, USA.
Chang C P
Rozenfeld S
Sauvageau G
Humphries R K
Lu M
Lawrence H J
Cleary M L
Largman C
References (48)
48 references, click to expand
  1. PBX2 and PBX3, new homeobox genes with extensive homology to the human proto-oncogene PBX1.
    Mol Cell Biol. 1991 Dec;11(12):6149-57 PMID: 1682799
  2. Crystal structure of an engrailed homeodomain-DNA complex at 2.8 A resolution: a framework for understanding homeodomain-DNA interactions.
    Cell. 1990 Nov 2;63(3):579-90 PMID: 1977522
  3. Cell type dependent transcription regulation by chick homeodomain proteins.
    Mech Dev. 1992 Mar;37(1-2):25-36 PMID: 1351400
  4. Cooperative DNA binding of the highly conserved human Hox 2.1 homeodomain gene product.
    New Biol. 1992 May;4(5):558-68 PMID: 1355360
  5. Differential DNA sequence recognition is a determinant of specificity in homeotic gene action.
    EMBO J. 1992 Nov;11(11):4059-72 PMID: 1356765
  6. NMR structure determination reveals that the homeodomain is connected through a flexible linker to the main body in the Drosophila Antennapedia protein.
    Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10738-42 PMID: 1359544
  7. Hoxb-4 (Hox-2.6) mutant mice show homeotic transformation of a cervical vertebra and defects in the closure of the sternal rudiments.
    Cell. 1993 Apr 23;73(2):279-94 PMID: 8097432
  8. extradenticle, a regulator of homeotic gene activity, is a homolog of the homeobox-containing human proto-oncogene pbx1.
    Cell. 1993 Sep 24;74(6):1101-12 PMID: 8104703
  9. Hoxa-2 mutant mice exhibit homeotic transformation of skeletal elements derived from cranial neural crest.
    Cell. 1993 Dec 31;75(7):1317-31 PMID: 7903600
  10. A homeotic transformation is generated in the rostral branchial region of the head by disruption of Hoxa-2, which acts as a selector gene.
    Cell. 1993 Dec 31;75(7):1333-49 PMID: 7903601
  11. Recognition of a DNA operator by a dimer composed of two different homeodomain proteins.
    EMBO J. 1994 Mar 15;13(6):1434-42 PMID: 7907979
  12. Fusion with E2A alters the transcriptional properties of the homeodomain protein PBX1 in t(1;19) leukemias.
    Oncogene. 1994 Jun;9(6):1641-7 PMID: 8183558
  13. Hox proteins have different affinities for a consensus DNA site that correlate with the positions of their genes on the hox cluster.
    Mol Cell Biol. 1994 Jul;14(7):4532-45 PMID: 7911971
  14. Expression of HOX homeogenes in human neuroblastoma cell culture lines.
    Differentiation. 1990 Oct;45(1):61-9 PMID: 1981366
  15. Alternative splicing of the HOX 2.2 homeobox gene in human hematopoietic cells and murine embryonic and adult tissues.
    Nucleic Acids Res. 1991 Feb 11;19(3):539-45 PMID: 1672751
  16. Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5.
    Nature. 1991 Apr 11;350(6318):473-9 PMID: 1673020
  17. Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia.
    Science. 1991 Jul 5;253(5015):79-82 PMID: 1676542
  18. Disruption of the Hox-1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expression.
    Cell. 1991 Sep 20;66(6):1105-19 PMID: 1680563
  19. The tcl-3 proto-oncogene altered by chromosomal translocation in T-cell leukemia codes for a homeobox protein.
    EMBO J. 1991 Oct;10(10):2905-10 PMID: 1717256
  20. Crystal structure of a MAT alpha 2 homeodomain-operator complex suggests a general model for homeodomain-DNA interactions.
    Cell. 1991 Nov 1;67(3):517-28 PMID: 1682054
  21. Mice with targeted disruptions in the paralogous genes hoxa-3 and hoxd-3 reveal synergistic interactions.
    Nature. 1994 Jul 28;370(6487):304-7 PMID: 7913519
  22. Homeodomain-DNA recognition.
    Cell. 1994 Jul 29;78(2):211-23 PMID: 8044836
  23. The DNA binding specificity of Ultrabithorax is modulated by cooperative interactions with extradenticle, another homeoprotein.
    Cell. 1994 Aug 26;78(4):603-15 PMID: 7915199
  24. extradenticle raises the DNA binding specificity of homeotic selector gene products.
    Cell. 1994 Aug 26;78(4):617-24 PMID: 7915200
  25. Interaction between two homeodomain proteins is specified by a short C-terminal tail.
    Nature. 1994 Sep 29;371(6496):429-32 PMID: 8090224
  26. Extradenticle protein is a selective cofactor for the Drosophila homeotics: role of the homeodomain and YPWM amino acid motif in the interaction.
    Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):739-43 PMID: 7846045
  27. Pbx proteins display hexapeptide-dependent cooperative DNA binding with a subset of Hox proteins.
    Genes Dev. 1995 Mar 15;9(6):663-74 PMID: 7729685
  28. Both Pbx1 and E2A-Pbx1 bind the DNA motif ATCAATCAA cooperatively with the products of multiple murine Hox genes, some of which are themselves oncogenes.
    Mol Cell Biol. 1995 Jul;15(7):3786-95 PMID: 7791786
  29. Segmental expression of Hoxb-1 is controlled by a highly conserved autoregulatory loop dependent upon exd/pbx.
    Cell. 1995 Jun 30;81(7):1031-42 PMID: 7600572
  30. Cooperative interactions between HOX and PBX proteins mediated by a conserved peptide motif.
    Mol Cell Biol. 1995 Aug;15(8):3989-97 PMID: 7623795
  31. The hexapeptide LFPWMR in Hoxb-8 is required for cooperative DNA binding with Pbx1 and Pbx2 proteins.
    Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9166-70 PMID: 7568094
  32. Hox gene products modulate the DNA binding activity of Pbx1 and Pbx2.
    Mech Dev. 1995 Jul;52(1):99-108 PMID: 7577680
  33. The carboxy-terminal tail of the homeo domain protein alpha 2 is required for function with a second homeo domain protein.
    Genes Dev. 1993 Oct;7(10):1862-70 PMID: 8104845
  34. At least three human homeoboxes on chromosome 12 belong to the same transcription unit.
    Nucleic Acids Res. 1988 Jun 24;16(12):5379-90 PMID: 2898768
  35. Hox-5.1 defines a homeobox-containing gene locus on mouse chromosome 2.
    Proc Natl Acad Sci U S A. 1988 Jul;85(13):4760-4 PMID: 2898782
  36. How eukaryotic transcriptional activators work.
    Nature. 1988 Oct 20;335(6192):683-9 PMID: 3050531
  37. Homeobox proteins as sequence-specific transcription factors.
    Cell. 1988 Nov 18;55(4):537-40 PMID: 2902929
  38. Expression of Hox-2.4 homeobox gene directed by proviral insertion in a myeloid leukemia.
    Nucleic Acids Res. 1989 Mar 11;17(5):1881-92 PMID: 2564662
  39. Structure and expression of a family of Ultrabithorax mRNAs generated by alternative splicing and polyadenylation in Drosophila.
    Genes Dev. 1989 Feb;3(2):243-58 PMID: 2565858
  40. Segmental expression of Hox-2 homoeobox-containing genes in the developing mouse hindbrain.
    Nature. 1989 Oct 5;341(6241):405-9 PMID: 2571936
  41. Lineage-restricted expression of homeobox-containing genes in human hematopoietic cell lines.
    Proc Natl Acad Sci U S A. 1989 Nov;86(21):8536-40 PMID: 2573064
  42. Coordinate expression of the murine Hox-5 complex homoeobox-containing genes during limb pattern formation.
    Nature. 1989 Dec 14;342(6251):767-72 PMID: 2574828
  43. The human HOX gene family.
    Nucleic Acids Res. 1989 Dec 25;17(24):10385-402 PMID: 2574852
  44. Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor.
    Cell. 1990 Feb 23;60(4):535-45 PMID: 1967982
  45. A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B ALL.
    Cell. 1990 Feb 23;60(4):547-55 PMID: 1967983
  46. The mouse Hox-1.4 gene: primary structure, evidence for promoter activity and expression during development.
    Development. 1989 Oct;107(2):343-59 PMID: 2576648
  47. Murine developmental control genes.
    Science. 1990 Jul 27;249(4967):374-9 PMID: 1974085
  48. Developmental defects of the ear, cranial nerves and hindbrain resulting from targeted disruption of the mouse homeobox gene Hox-1.6.
    Nature. 1992 Feb 6;355(6360):516-20 PMID: 1346922
Article Info
Journal
Nucleic acids research
Abbr.
Nucleic Acids Res
ISSN
0305-1048
DOI
10.1093/nar/24.5.898
Published
1996-03-01
Pages
898-906
Language
English
Region
England
NLM ID
0411011
PMCID
PMC145726
Subset
IM
Grants
NCI NIH HHS · CA42971,MLC · United States
NIDDK NIH HHS · N44DK-3-2219,CL · United States
External Links
PubMed source DOI: 10.1093/nar/24.5.898 PMC Full Text View journal details
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