Crystal structure of a MATα2 homeodomain-operator complex suggests a general model for homeodomain-DNA interactions

Wolberger, Cynthia; Vershon, Andrew K.; Liu, Beishan; Johnson, Alexander D.; Pabo, Carl O.

doi:10.1016/0092-8674(91)90526-5

Cited by 546 publications

(544 citation statements)

References 27 publications

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“…B4-3, Figure 5) decreased the transforming potential of mutant protein ®vefold when compared to the wild type HOXB4 (Figure 5). To disrupt the homeodomain/DNA interactions without compromising the conformation of HOXB4 protein we substituted the highly conserved asparagine-51 within helix three of the homeodomain, reported to represent a direct contact point between the homeodomains and the target DNA sequences (Kissinger et al, 1990;Wolberger et al, 1991), with alanine (mutant no. B4-4, Figure 5).…”

Section: Pbx1 Enhances Tumor Growth Induced By Hoxb4mentioning

confidence: 99%

Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1

et al. 1998

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The products of PBX homeobox genes, which were initially discovered in reciprocal translocations occurring in human leukemias, have been shown to cooperate in the in vitro DNA binding with HOX proteins. Despite the growing body of data implicating Hox genes in the development of various cancers, little is known about the role of HOX ± PBX interactions in the regulation of proliferation and induction of transformation of mammalian cells. We build on the existing model of Hoxinduced transformation of Rat-1 cells to show that both cellular transformation and proliferation induced by Hoxb4 and Hoxb3 are greatly modulated by the levels of available PBX1 present in these cells. Furthermore, we show that the transforming capacity of these two HOX proteins depends on their conserved tetrapeptide and homeodomain regions which mediate binding to PBX and DNA, respectively. Taken together, results of this study demonstrate that cooperation between HOX and PBX proteins modulates cellular proliferation and strongly suggest that cooperative DNA binding by these two groups of proteins represent the basis for Hoxinduced cellular transformation.

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Section: Pbx1 Enhances Tumor Growth Induced By Hoxb4mentioning

confidence: 99%

Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1

et al. 1998

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“…The interactions between homeodomains and DNA have been extensively analyzed by foot-printing methods and gel shift assays [6][7][8][9][10][11][12][13][14]. Direct structural analysis of the complexes has also been performed with NMR and X-ray [15][16][17][18][19]. The results indicated that a homeodomain binds to a specific sequence of less than 10 bp.…”

Section: Introductionmentioning

confidence: 99%

Kinetics of binding of Antp homeodomain to DNA analyzed by measurements of surface plasmon resonance

Seimiya¹,

Kurosawa²

1996

FEBS Letters

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The kinetics of binding of the Antp homeodomain to three kinds of DNA fragment were analyzed by measurements of surface plasmon resonance at various temperatures. Non-specific and specific binding of the homeodomain to DNA was examined. In the case of non-specific binding, the association rate constant (kass) was estimated to be 1.41-2.62X 105 M -1 s -1 and the dissociation rate constant (kdiss) was 1.36-3.10 X 10 -2 s -1, thus, the dissociation constant (KI)) was 0.847-1.72 × 10 7 M. The association seemed to be driven by entropy. In the case of specific binding, by contrast, the enthalpy term seemed to contribute more to the binding than did the entropy term. The kass was 2.04-2.59X105 M -1 s -1 and the kdiss was 0.759-1.16X10 -3 s -1, thus, the /to was 2.93-5.69X 10 -9 M. These values were measured under the condition of 150 mM NaCl. Both interactions were strongly dependent on the concentration of NaC1. The /to at 50 mM NaCI became several tens of times smaller than those at 150 mM. Possible reasons for the differences between non-specific and specific interactions are discussed.

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“…The N-terminal domain of the LexA repressor is considerably different in that it does not contain a canonical HTH motif. Trihelix-containing DBDs with similarities to the y6 resolvase DBD have been structurally characterized in eukaryotes and include the antennapedia homeodomain (Qian et al, 1989), the engrailed homeodomain (Kissinger et al, 1990), the homeodomain of the a 2 repressor (Wolberger et al, 1991), and repeat-3 of the c-Myb protein (Ogata et al, 1992). The POUH domain in Oct-1, Oct-2, and Pit-1 makes contacts to the DNA on the face opposite the dimeric POUS domain (Poellinger et al, 1989;Ingraham et al, 1990;Verrijzer et al, 1990;Klemm et al, 1994), as do the 2 domains of the resolvases and invertases.…”

Section: Structure-function Of the Dna Binding Domain Of Y6 Resolvasementioning

confidence: 99%

Determination of the structure of the DNA binding domain of γ^Δ resolvase in solution

1994

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The DNA binding domain (DBD) of y6 resolvase (residues 141-183) is responsible for the interaction of this sitespecific DNA recombinase with consensus site DNA within the y6 transposable element in Escherichia coli. Based on chemical-shift comparisons, the proteolytically isolated DBD displays side-chain interactions within a hydrophobic core that are highly similar to those of this domain when part of the intact enzyme (Liu T, Liu DJ, DeRose EF, Mullen GP, 1993, JBiol Chem 268:16309-16315). The structure of the DBD in solution has been determined using restraints obtained from 2-dimensional proton NMR data and is represented by 17 conformers. Experimental restraints included 458 distances based on analysis of nuclear Overhauser effect connectivities, 17 $ and x1 torsion angles based on analysis of couplings, and 17 backbone hydrogen bonds determined from NH exchange data.With respect to the computed average structure, these conformers display an RMS deviation of 0.67 A for the heavy backbone atoms and 1.49 A for all heavy atoms within residues 149-180. The DBD consists of 3 a-helices comprising residues D149-Q157, S162-T167, and R172-N183. Helix3 and helix-3 form a backbone fold, which is similar to the canonical helix-turn-helix motif. The conformation of the NH2-terminaI residues, G141-R148, appears flexible in solution. A hydrophobic core is formed by side chains donated by essentially all hydrophobic residues within the helices and turns. Helix-1 and helix-3 cross with a right-handed folding topology. The structure is consistent with a mechanism of DNA binding in which contacts are made by the hydrophilic face of helix-3 in the major groove and the amino-terminal arm in the minor groove. This structure represents an important step toward analysis of the mechanism of DNA interaction by y6 resolvase and provides initial structure-function comparisons among the divergent DBDs of related resolvases and invertases.Keywords: DNA recombinase; helix-turn-helix; NMR; recognition helix y6 Resolvase is representative of a family of DNA recombinases for which significant structural and functional information regarding site-specific DNA recombination has been obtained. However, until recently, no structural information had been available on the DNA binding domains for this protein family.The y6 resolvase protein, through formation of a multimeric complex termed a synaptosome, catalyzes the second step of y6 DNA transposition in Escherichia coli (reviewed by . In this step, a negatively supercoiled plasmid DNA containing 2 copies of the y6 transposon is converted to catenated circular DNA products, each of which contains a single copy of the transposon. The topolog-

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Crystal structure of a MATα2 homeodomain-operator complex suggests a general model for homeodomain-DNA interactions

Cited by 546 publications

References 27 publications

Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1

Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1

Kinetics of binding of Antp homeodomain to DNA analyzed by measurements of surface plasmon resonance

Determination of the structure of the DNA binding domain of γ^Δ resolvase in solution

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Crystal structure of a MATα2 homeodomain-operator complex suggests a general model for homeodomain-DNA interactions

Cited by 546 publications

References 27 publications

Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1

Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1

Kinetics of binding of Antp homeodomain to DNA analyzed by measurements of surface plasmon resonance

Determination of the structure of the DNA binding domain of γΔ resolvase in solution

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Determination of the structure of the DNA binding domain of γ^Δ resolvase in solution