Sequence and structure continuity of evolutionary importance improves protein functional site discovery and annotation

Wilkins, Angela D.; Lua, Rhonald C.; Erdin, Serkan; Ward, R. Matthew; Lichtarge, Olivier

doi:10.1002/pro.406

Cited by 26 publications

(32 citation statements)

References 72 publications

(91 reference statements)

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“…This complements the original notion of ET clusters (Lichtarge et al, 1996) with a mathematically simple interpretation that lends itself to computation via the Laplacian operator of a graph. This discrete Laplacian operator is fundamental to networks (Chung, 1997), and here it enables optimization in sequence selection better than the diverse measures of clustering used before (Wilkins et al, 2010). These were entirely empirical and useful to suggest the simplifying notion of smoothness.…”

Section: Discussionmentioning

confidence: 99%

“…The dataset of functional determinants was taken from a previous work (Wilkins et al, 2010). The gold standard functional sites for protein–ligand interactions are defined by the database PDBsum (Laskowski et al, 2005).…”

Section: Methodsmentioning

confidence: 99%

“…The function annotation tests included past query and target sets (Ward et al, 2008; Wilkins et al, 2010). The query set included 1217 structural genomics enzymes annotated to the third or fourth level of the Enzyme Commission (EC) classification.…”

Section: Methodsmentioning

confidence: 99%

“…Strong epistatic interactions occur between contact residues (Ortlund et al, 2007), presumably because function and adaptation are intimately related to mutual interaction and variation of physically neighboring residues. Indeed, improving the clustering quality of evolutionarily important residues improves predictions of functional sites (Mihalek et al, 2006a, b; Wilkins et al, 2010). In that light, the clustering of these residues simply reflects the fundamental epistatic coupling of neighbors.…”

Section: Introductionmentioning

confidence: 99%

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Accounting for epistatic interactions improves the functional analysis of protein structures

Wilkins¹,

Marciano²,

Erdin³

et al. 2013

Bioinformatics

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Motivation: The constraints under which sequence, structure and function coevolve are not fully understood. Bringing this mutual relationship to light can reveal the molecular basis of binding, catalysis and allostery, thereby identifying function and rationally guiding protein redesign. Underlying these relationships are the epistatic interactions that occur when the consequences of a mutation to a protein are determined by the genetic background in which it occurs. Based on prior data, we hypothesize that epistatic forces operate most strongly between residues nearby in the structure, resulting in smooth evolutionary importance across the structure.Methods and Results: We find that when residue scores of evolutionary importance are distributed smoothly between nearby residues, functional site prediction accuracy improves. Accordingly, we designed a novel measure of evolutionary importance that focuses on the interaction between pairs of structurally neighboring residues. This measure that we term pair-interaction Evolutionary Trace yields greater functional site overlap and better structure-based proteome-wide functional predictions.Conclusions: Our data show that the structural smoothness of evolutionary importance is a fundamental feature of the coevolution of sequence, structure and function. Mutations operate on individual residues, but selective pressure depends in part on the extent to which a mutation perturbs interactions with neighboring residues. In practice, this principle led us to redefine the importance of a residue in terms of the importance of its epistatic interactions with neighbors, yielding better annotation of functional residues, motivating experimental validation of a novel functional site in LexA and refining protein function prediction.Contact: lichtarge@bcm.eduSupplementary information: Supplementary data are available at Bioinformatics online.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Accounting for epistatic interactions improves the functional analysis of protein structures

Wilkins¹,

Marciano²,

Erdin³

et al. 2013

Bioinformatics

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show abstract

“…Residues that are invariant among the widely divergent branches of evolution are expected to have a larger functional impact than other residues that vary among closely related species (Lichtarge et al, 1996). The distribution of evolutionarily important residues is far from random when mapped onto the protein structure (Lichtarge et al, 1996; Baranski et al, 1999; Madabushi et al, 2002), forming clusters that overlap with known functional sites (Madabushi et al, 2002; Baameur et al, 2010; Lichtarge et al, 2003; Yao et al, 2003; Sowa et al, 2000; Onrust et al, 1997; Chiba et al, 2006; Madabushi et al, 2004; Wilkins et al, 2013; Wilkins et al, 2010) from which one may then automatically extract 3D motifs useful for transferring functional annotation between proteins on the scale of the entire structural proteome (Venner et al, 2010; Amin et al, 2013; Erdin et al, 2013). These 3D motifs consists of five or six residues identified by ET, they do not rely on prior knowledge of the molecular basis of any function, and a recent study shows that they can be accurate enough for bona fide prediction of both catalytic activity and substrates (Amin et al, 2013).…”

Section: Current Methods For Ppismentioning

confidence: 99%

Prediction and redesign of protein–protein interactions

Lua

Marciano

Katsonis

et al. 2014

Progress in Biophysics and Molecular Biology

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Understanding the molecular basis of protein function remains a central goal of biology, with the hope to elucidate the role of human genes in health and in disease, and to rationally design therapies through targeted molecular perturbations. We review here some of the computational techniques and resources available for characterizing a critical aspect of protein function – those mediated by protein–protein interactions (PPI). We describe several applications and recent successes of the Evolutionary Trace (ET) in identifying molecular events and shapes that underlie protein function and specificity in both eukaryotes and prokaryotes. ET is a part of analytical approaches based on the successes and failures of evolution that enable the rational control of PPI.

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An analysis approach to identify specific functional sites in orthologous proteins using sequence and structural information: Application to neuroserpin reveals regions that differentially regulate inhibitory activity

et al. 2014

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The analysis of sequence conservation is commonly used to predict functionally important sites in proteins. We have developed an approach that first identifies highly conserved sites in a set of orthologous sequences using a weighted substitution-matrix-based conservation score and then filters these conserved sites based on the pattern of conservation present in a wider alignment of sequences from the same family and structural information to identify surface-exposed sites. This allows us to detect specific functional sites in the target protein and exclude regions that are likely to be generally important for the structure or function of the wider protein family. We applied our method to two members of the serpin family of serine protease inhibitors. We first confirmed that our method successfully detected the known heparin binding site in antithrombin while excluding residues known to be generally important in the serpin family. We next applied our sequence analysis approach to neuroserpin and used our results to guide site-directed polyalanine mutagenesis experiments. The majority of the mutant neuroserpin proteins were found to fold correctly and could still form inhibitory complexes with tissue plasminogen activator (tPA). Kinetic analysis of tPA inhibition, however, revealed altered inhibitory kinetics in several of the mutant proteins, with some mutants showing decreased association with tPA and others showing more rapid dissociation of the covalent complex. Altogether, these results confirm that our sequence analysis approach is a useful tool that can be used to guide mutagenesis experiments for the detection of specific functional sites in proteins.

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Sequence and structure continuity of evolutionary importance improves protein functional site discovery and annotation

Cited by 26 publications

References 72 publications

Accounting for epistatic interactions improves the functional analysis of protein structures

Accounting for epistatic interactions improves the functional analysis of protein structures

Prediction and redesign of protein–protein interactions

An analysis approach to identify specific functional sites in orthologous proteins using sequence and structural information: Application to neuroserpin reveals regions that differentially regulate inhibitory activity

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