Crystal structure of a paired domain-DNA complex at 2.5 å resolution reveals structural basis for pax developmental mutations

Xu, Wenqing; Rould, Mark A.; Jun, Susie; Desplan, Claude; Pabo, Carl O.

doi:10.1016/0092-8674(95)90518-9

Cited by 309 publications

(327 citation statements)

References 46 publications

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“…2c) How does this mutation affect 5aCON binding? The Arg-128 residue may stabilize the protein-DNA interaction by directly contacting DNA, which is consistent with computer modelling (Xu et al 1995), while the mutated Cys residue may destabilize their interaction, for instance, by disulphide bond formation. To distinguish between these possibilities, we mutated the Arg-128 to residues other than Cys.…”

Section: Dna-binding Activity Of the C-terminal Subdomain Of Pax6 Paisupporting

confidence: 81%

“…The former has generally been considered to be important for specific DNA-binding (Chalepakis et al 1991;Treisman et al 1991). Recent X-ray structural analysis of paired has revealed that these subdomains contain helix-turn-helix motifs resembling the Hin recombinase, and are separated by a b-turn, and that the NTS and the b-turn make contacts with DNA (Xu et al 1995). In contrast to the other paired domain-containing proteins, however, both NTS and CTS of the Pax6 paired domain are suggested to have distinct DNA-binding activities (Epstein et al 1994b).…”

Section: Introductionmentioning

confidence: 99%

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Autoregulation of Pax6 transcriptional activation by two distinct DNA‐binding subdomains of the paired domain

Yamaguchi

Sawada

Yamada³

et al. 1997

Genes to Cells

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Section: Dna-binding Activity Of the C-terminal Subdomain Of Pax6 Paisupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Autoregulation of Pax6 transcriptional activation by two distinct DNA‐binding subdomains of the paired domain

Yamaguchi

Sawada

Yamada³

et al. 1997

Genes to Cells

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show abstract

“…Top : schematic representation of the structure of the paired domain with the PAI and RED subdomains ; α-helical regions as described by Xu et al [10] are indicated. Bottom : all the oligonucleotides used in this study are aligned to the Pax-8 consensus sequence defined previously [11,12].…”

Section: Figure 1 Model Of the Pax-8 Prd Domain-c-sequence Interactiomentioning

confidence: 99%

“…Several studies have demonstrated that the Prd domain consists functionally of two distinct subdomains [8,9]. The crystal structure resolution of the Prd domain of the paired protein bound to DNA has also demonstrated the presence of two structurally independent subdomains, each containing a helix-turn-helix motif, joined by a linker region [10]. Recently, the N-and Cterminal subdomains have been named PAI and RED respectively [11].…”

Section: Introductionmentioning

confidence: 99%

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Co-operation between the PAI and RED subdomains of Pax-8 in the interaction with the thyroglobulin promoter

Pellizzari

Tell

Damante

1999

Biochemical Journal

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Pax proteins are transcription factors that play an important role in the differentiation of several cell types. These proteins bind to specific DNA sequences through the paired domain. This evolutionarily conserved element is composed of two subdomains (PAI and RED), located at the N-and C-terminals, respectively. Due to the presence of these two subdomains, Pax proteins may recognize DNA in different modes, a possibility that has not been exhaustively explored yet. The C site of the thyroglobulin promoter is bound by the thyroid-specific transcription factor Pax-8. In this study we have characterized the mode by which the Pax-8 paired domain interacts with the C site. Results allow the identification of the respective positions of the PAI and RED subdomains when the full-length protein is bound to the C site. The binding of the isolated PAI and RED subdomains to the C site and to several related mutants was also evaluated. Both subdomains interact with DNA as a monomer and display a

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Structure-based prediction of DNA target sites by regulatory proteins

1999

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Regulatory proteins play a critical role in controlling complex spatial and temporal patterns of gene expression in higher organism, by recognizing multiple DNA sequences and regulating multiple target genes. Increasing amounts of structural data on the protein-DNA complex provides clues for the mechanism of target recognition by regulatory proteins. The analyses of the propensities of base-amino acid interactions observed in those structural data show that there is no one-to-one correspondence in the interaction, but clear preferences exist. On the other hand, the analysis of spatial distribution of amino acids around bases shows that even those amino acids with strong base preference such as Arg with G are distributed in a wide space around bases. Thus, amino acids with many different geometries can form a similar type of interaction with bases. The redundancy and structural flexibility in the interaction suggest that there are no simple rules in the sequence recognition, and its prediction is not straightforward. However, the spatial distributions of amino acids around bases indicate a possibility that the structural data can be used to derive empirical interaction potentials between amino acids and bases. Such information extracted from structural databases has been successfully used to predict amino acid sequences that fold into particular protein structures. We surmised that the structures of protein-DNA complexes could be used to predict DNA target sites for regulatory proteins, because determining DNA sequences that bind to a particular protein structure should be similar to finding amino acid sequences that fold into a particular structure. Here we demonstrate that the structural data can be used to predict DNA target sequences for regulatory proteins. Pairwise potentials that determine the interaction between bases and amino acids were empirically derived from the structural data. These potentials were then used to examine the compatibility between DNA sequences and the protein-DNA complex structure in a combinatorial "threading" procedure. We applied this strategy to the structures of protein-DNA complexes to predict DNA binding sites recognized by regulatory proteins. To test the applicability of this method in target-site prediction, we examined the effects of cognate and noncognate binding, cooperative binding, and DNA deformation on the binding specificity, and predicted binding sites in real promoters and compared with experimental data. These results show that target binding sites for several regulatory proteins are successfully predicted, and our data suggest that this method can serve as a powerful tool for predicting multiple target sites and target genes for regulatory proteins.

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Crystal structure of a paired domain-DNA complex at 2.5 å resolution reveals structural basis for pax developmental mutations

Cited by 309 publications

References 46 publications

Autoregulation of Pax6 transcriptional activation by two distinct DNA‐binding subdomains of the paired domain

Autoregulation of Pax6 transcriptional activation by two distinct DNA‐binding subdomains of the paired domain

Co-operation between the PAI and RED subdomains of Pax-8 in the interaction with the thyroglobulin promoter

Structure-based prediction of DNA target sites by regulatory proteins

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