Correlated Evolutionary Pressure at Interacting Transcription Factors and DNA Response Elements Can Guide the Rational Engineering of DNA Binding Specificity

Raviscioni, Michele; Gu, Peili; Sattar, Minawar; Cooney, Austin J.; Lichtarge, Olivier

doi:10.1016/j.jmb.2005.04.054

Cited by 24 publications

(21 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Combined with the fact that several folds have evolved to perform multiple functions at analogous sites (28)(29)(30)(31)(32), this observation is consistent with the notion that the putative binding site is coded in the fold [more precisely the energetic balance within the fold (20)], and that not all possible folds will necessarily have the thermodynamic attributes for an effective binding site. If this were the case, folds with little or no potential for a binding site, although possibly appearing at various stages of evolution, may not survive the selection process.…”

Section: Discussionsupporting

confidence: 69%

Functional residues serve a dominant role in mediating the cooperativity of the protein ensemble

Liu

Whitten

Hilser

2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Conformational fluctuations in proteins have emerged as a potentially important aspect of biological function, although the precise relationship and the implications have yet to be fully explored. Numerous studies have reported that the binding of ligand can influence fluctuations. However, the role of the binding site in mediating these fluctuations is not known. Of particular interest is whether in addition to serving as structural scaffolds for recognition and catalysis, active-site residues may also play a role in modulating the cooperative network. To address this question, we employ an experimentally validated ensemble-based description of proteins to elucidate the extent to which perturbations at different sites can influence the cooperative network in the protein. Applying this method to a database of test proteins, it is found statistically that binding sites are located in regions most able to affect the cooperative network, even for cooperative interactions between residues distant to the binding sites. This indicates that the conformational manifold under native conditions is determined by the network of cooperative interactions within the protein and suggests that proteins have evolved to use these conformational fluctuations in carrying out their functions. Furthermore, because the energetic coupling pattern calculated for each protein is robust and relatively insensitive to sequence, these studies further suggest that binding sites evolved in regions of the protein that are inherently poised to take advantage of the fluctuations in the native structure.COREX analysis ͉ energetic coupling ͉ native state ensemble ͉ thermodynamic linkage B iological work in living organisms is mediated primarily through the use of protein molecules. Knowledge of the means by which proteins facilitate this work is of paramount importance to an understanding of function as well as the diseases that result from aberrant function. Of particular interest in recent years has been the observation that proteins are highly dynamic molecules that experience dramatic conformational excursions from the canonical high-resolution structure (1-3). In addition, it has also become clear that conformational dynamics play an important role in determining the ability of proteins to perform such diverse tasks as catalysis, allosterism, and signal transduction (4-6).The observation that protein conformational fluctuations play an important role in function suggests that functional sites in proteins may be uniquely coupled to structural fluctuations (7-9) and thus identifiable by how perturbations at these sites affect the conformational manifold. Here we use an ensemblebased model of the protein to explore this issue. By identifying a statistically significant difference in the response of the ensemble to perturbations at active sites of proteins, as determined from a representative test set, we find that binding sites play a unique role in influencing the cooperative network within proteins. This suggests that binding sites have been pre...

show abstract

Section: Discussionsupporting

confidence: 69%

Functional residues serve a dominant role in mediating the cooperativity of the protein ensemble

Liu

Whitten

Hilser

2007

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…34 Indeed, using the structure of the glucocorticoid receptor DBD-DNA complex as a guide, Raviscioni et al predicted correctly that Glu104Gly and Gly108Val mutations within the major groovebinding helix of the core domain would alter the sequence-specific DNA contacts formed by LRH-1. 35 By introducing sequence-specific hydrogen bonds as well as steric clashes, these mutations changed the preference of LRH-1 from AGGCCA to the canonical steroid receptor hexad AGAACA.…”

Section: Protein-dna Contactsmentioning

confidence: 99%

Crystal Structure of the Human LRH-1 DBD–DNA Complex Reveals Ftz-F1 Domain Positioning is Required for Receptor Activity

Solomon

Hager

Safi

et al. 2005

Journal of Molecular Biology

View full text Add to dashboard Cite

“…12 Third, comparisons of protein and cognate DNA sequences within families, including mutual information and evolutionary trace analyses, have revealed protein-DNA sequence covariations and correlations in evolutionary importance that correspond to known or probable direct contacts. 5,7,14,15 Detectable covariations can form the basis for partial evolutionary recognition codes for a given family, 5,7 affording an improved understanding of evolutionary mechanism, as well as applications to the design, engineering and prediction of functional specificity. 16 Identification of natural protein-DNA sequence covariations depends upon availability of a significant database of homologous cognate pairs.…”

Section: Introductionmentioning

confidence: 99%

Reengineering Cro Protein Functional Specificity with an Evolutionary Code

Hall

Vaughn

Begaye

et al. 2011

Journal of Molecular Biology

View full text Add to dashboard Cite

Correlated Evolutionary Pressure at Interacting Transcription Factors and DNA Response Elements Can Guide the Rational Engineering of DNA Binding Specificity

Cited by 24 publications

References 45 publications

Functional residues serve a dominant role in mediating the cooperativity of the protein ensemble

Functional residues serve a dominant role in mediating the cooperativity of the protein ensemble

Crystal Structure of the Human LRH-1 DBD–DNA Complex Reveals Ftz-F1 Domain Positioning is Required for Receptor Activity

Reengineering Cro Protein Functional Specificity with an Evolutionary Code

Contact Info

Product

Resources

About