Identification of specificity determining residues in peptide recognition domains using an information theoretic approach applied to large-scale binding maps
© Yip et al; licensee BioMed Central Ltd. 2011
Received: 26 July 2011
Accepted: 11 August 2011
Published: 11 August 2011
Peptide Recognition Domains (PRDs) are commonly found in signaling proteins. They mediate protein-protein interactions by recognizing and binding short motifs in their ligands. Although a great deal is known about PRDs and their interactions, prediction of PRD specificities remains largely an unsolved problem.
We present a novel approach to identifying these Specificity Determining Residues (SDRs). Our algorithm generalizes earlier information theoretic approaches to coevolution analysis, to become applicable to this problem. It leverages the growing wealth of binding data between PRDs and large numbers of random peptides, and searches for PRD residues that exhibit strong evolutionary covariation with some positions of the statistical profiles of bound peptides. The calculations involve only information from sequences, and thus can be applied to PRDs without crystal structures. We applied the approach to PDZ, SH3 and kinase domains, and evaluated the results using both residue proximity in co-crystal structures and verified binding specificity maps from mutagenesis studies.
Our predictions were found to be strongly correlated with the physical proximity of residues, demonstrating the ability of our approach to detect physical interactions of the binding partners. Some high-scoring pairs were further confirmed to affect binding specificity using previous experimental results. Combining the covariation results also allowed us to predict binding profiles with higher reliability than two other methods that do not explicitly take residue covariation into account.
The general applicability of our approach to the three different domain families demonstrated in this paper suggests its potential in predicting binding targets and assisting the exploration of binding mechanisms.
1.1 Protein recognition domains (PRDs) and specificity determining residues (SDRs)
Peptide recognition domains are key elements on proteins with many roles in central signaling pathways . PRDs are involved in many diseases and are a focus of drug discovery efforts . Some viruses co-opt host PRDs via mimicry, emphasizing their relevance to human diseases [3–5]. Representative PRDs include PDZ, SH3 and kinase domains. These domains recognize short (usually around seven to ten amino acids long) motifs in their target proteins. Such motifs often lie in unstructured regions  and hence resemble peptides in their conformational flexibility. In particular, PDZ domains recognize hydrophobic C-terminal tails, SH3 domains recognize proline-rich motifs, and kinase domains bind several different classes of motifs; for instance, basophilic kinases bind arginine-rich motifs. As many PRDs are well behaved in solution, they are ideal model systems for studying protein-protein interactions and ligand binding specificity. New approaches, namely phage display , protein or peptide arrays [8–10] and oriented peptide libraries  have greatly facilitated the measurement of specificities and produced an hitherto unimaginable wealth of binding data. Despite these advances, the residues within the domains that determine their binding specificity have only partly been elucidated. Such specificity determining residues (SDRs) [12, 13] can be identified using dedicated experiments involving site-directed mutagenesis and subsequent measurement of specificity. For example, recent studies have directly tested effects of point mutations in kinases  and PDZ domains . However, because of the size of the sequence space to be covered, exhaustive experimental search is infeasible. While co-crystal structures of PRDs with the bound ligand are often used to prioritize residues, identification of SDRs remains a complex problem: on the one hand, close proximity to the ligand does not necessarily implicate a residue in specificity determination. On the other hand, a residue that is far away from the ligand can also affect specificity due to secondary effects on the binding site [13, 15]. Hence, computational methods are needed to select and prioritize the positions to be tested through mutagenesis. Meanwhile, the aforementioned wealth of specificity data offers ample resources to be computationally analyzed for information about SDRs.
Currently, there are two major classes of computational approaches for SDR identification: first, there are structure driven approaches, making use of physical properties from protein structures, such as the hydration site free energies displaced by ligand atoms upon binding . The second class of approaches adopts a statistical approach, and identifies SDRs by looking for sites that are conserved across or within functional groups , or more conserved in orthologs than paralogs . Our method also takes on a statistical approach, the systematic nature of which enables the potential identification of non-local interactions between residues that are significant for peptide binding. Due to the lack of large-scale binding data previously, most current statistical methods attempt to detect SDRs based only on conservation signals from multiple sequence alignments of the PRDs. These predictions are noisy as the conservation of a residue could be due to roles other than binding specificity determination. Hence, these approaches do not make optimal use of currently available data. Conversely, utilizing the information about the actual bound peptide profiles from the recent large-scale binding datasets has the potential to boost the power of new predictions. In this paper we demonstrate how these new datasets can be incorporated in the search for SDRs. Previously we explored this idea using a proof-of-principle correlation-based method as part of a larger experimental study . Here, we develop a new approach that is based on a novel formalism of mutual information.
1.2 Traditional and generalized covariation methods
Our approach is based on the notion that SDRs would covary with the binding specificity. The concept of covariation has first been used to study internal residue contacts in proteins [18, 19]. It has subsequently been used in the identification of energetically coupled residues , coevolution of proteins with their interaction partners [21–25], protein fold , functionally or structurally coupled residues within a protein [27, 28] and protein fusion . The basic idea is to look for two sites in a multiple sequence alignment (MSA), or a pair of MSAs when studying the interaction between two proteins, that exhibit coordinated changes. Such covariation could suggest functional or structural dependency between the two sites, as there exists evolutionary pressure against their independent evolution. In the context of SDR identification, the covariation between a residue in the PRD and a residue in the bound peptide could imply its role in mediating the binding.
2.1 Entropy and mutual information
where log 0 is defined as 0, the asymptotic value of log(x) towards 0. In the general definition of entropy, the base of the logarithm can be set to any value. In analyzing protein sequences, where is the set of 20 amino acid residues, it is convenient to use 20 as the base so that the entropy value is always between zero and one .
2.2 Adapting mutual information to the identification of SDRs
where is the indicator function with and .
The entropy can be interpreted as the uncertainty of which residue we would encounter at the site if we randomly draw a sequence from the MSA, where uncertainty here is mathematically quantified by the number of bits needed to encode the information on average. A completely conserved site has an entropy of zero, and indeed there is no uncertainty as the residue being drawn must always be the same. A site with equal probability of all 20 residues has the maximum possible entropy of one. In general, a more diverse site has a larger entropy.
The joint entropy measures the uncertainty of which two residues we would encounter at MSA site j and PWM site k if we randomly draw a sequence from the MSA and get its corresponding PWM.
Finally, we can compute the mutual information between MSA site j and PWM site k using Formula 3. Since H (X, Y) is the uncertainty of the two sites that persists even when we consider them together, subtracting it from H (X) + H (Y) gives the uncertainty that is eliminated by considering the two sites together. In other words, mutual information measures the information shared by the two sites. A larger mutual information indicates a stronger dependency between them. This could indicate a functional or structural relationship between the two sites. For example, it could suggest that the two sites coevolve in the sense that when the residue at the MSA site is changed, binding strength is restored by having a corresponding change at the PWM site.
2.3 Handling uneven sequence representation
Entropy, joint-entropy and mutual information can then be calculated using these new definitions of probabilities.
2.4 Handling uneven site conservation
A hypothetical example MSA that illustrates the problem of uneven site conservation.
We have also tried handling the problem using a statistical test. Specifically, we used mutual information as the test statistic to calculate how unlikely it is to get a mutual information at least as large as the observed one under the null hypothesis that the two sites are independent. The distribution of mutual information can be obtained by permuting the residues of a site, or by using a chi-square approximation. It was shown that when n is large, (2 ln 2n)MI(X, Y) tends to have a chi-square distribution with degrees of freedom [46, 47]. It turns out that the results based on this statistical test were not better than using the simple normalization approach. We thus focus on the use of the uncertainty coefficient measure in handling uneven site conservation in the remaining of this paper.
Table 1 also demonstrates the tradeoff between the mutual information between two sites and their individual conservation, both of which are indicators of their functional importance. One may try to derive a measure that takes both into account, similar to what the Sequence Harmony method handles both the conservation and similarity of two groups of residues simultaneously, for the problem of identifying important residues that determine the functional differences of protein subfamilies . We leave the derivation of a new covariation measure to a future study.
2.5 Predicting the PWMs of bound peptides
One important use of the covariation scores is to contribute towards predicting the PWMs of bound peptides. This can be done by aggregating the detected covariation signals. Suppose we are given a new PRD sequence (the (n + 1)th sequence) of the MSA M without the corresponding PWM of its bound peptides. We would like to predict the PWM based on the n + 1 sequences in the MSA and the n known PWMs. We investigate the use of the covariation scores in this problem by comparing a prediction method that considers site covariation with two methods that do not.
where the uncertainty coefficient UC(A j , W k ) is computed based on the n original sequences.
We also investigated if prediction accuracy can be improved by using a more complex model. Specifically, we treated each MSA site as a categorical attribute and trained a regression tree model for each probability value in the PWM. The models were then applied to the new sequence to predict the PWM of its bound peptides. We implemented this method using REPTree of the Weka package .
To evaluate the effectiveness of the different methods, we performed left-out validation as follows. Each time, we drew a random sample of PRDs to form the testing set. Each sequence in the testing set took turn to take the role of the (n + 1)th sequence. The sequences not included in the sample formed the training set. These sequences were used to compute covariation scores and train prediction models. The procedure was repeated 1,000 times for PDZ and SH3 and 50 times for kinase (due to the long running time) with different random training-testing splits, and the average performance of the trained models on the testing sets was recorded. To eliminate near-identical sequences in the training and testing sets, for sequences with 90% or more identity, we kept only one of them in the dataset before making the training-testing splits. As most of the synthetic PDZ sequences (described below) are highly similar, we excluded this dataset from this part of study.
where and are the predicted and actual PWMs for the bound peptides of the testing sequence, respectively, and the inner summation is taken over all 20 amino acid residues.
3.1 Application of the method to PDZ, SH3 and kinase domains
3.1.1 Natural PDZ domains
We obtained 33 class I human and worm PDZ domains from a recent large-scale study on the specificity map of PDZ domains . Class I PDZ domains were defined by two positions on the ligand, with the pattern X[T/S]X ϕ COOH , where X and ϕ represent a residue and a hydrophobe, respectively. In the same study, a number of SDRs were experimentally determined, allowing us to validate our prediction results. We focused on only one class of domains as the sequences in different classes are difficult to align due to divergence. The pairwise sequence identity ranges from 0.13 to 0.87, with an average of 0.28.
The binding profile of each domain, in the form of a PWM, was obtained from phage display experiments that expressed a random library of C-terminal peptides . The domains were then aligned to form an MSA using ClustalW  followed by manual corrections of some obvious errors. A phylogenetic tree of the MSA sequences was constructed using Biopython's Nexus module , and the tree was used to produce sequence weights according to a described algorithm . The uncertainty coefficient between each MSA site and each site of the peptide PWMs was computed. To reduce noise and eliminate highly conserved sites that provide little information about covariation, we considered only sites with no gaps  and the most frequent residue occupying no more than half of the total sequence weights. This filtering was also applied to the other domain families described below.
The remaining unfiltered site pairs were then evaluated in two ways. First, their uncertainty coefficients were compared to their physical distances in the co-crystal structure 2H2C of ligand-bound human ZO-1 PDZ1 domain  in PDB . Although proximity does not necessarily mean functional or structural dependency, it is usually used as a quick check in covariation studies [18, 27, 29, 33]. It also provides a complete and unbiased alternative to the more costly experimental validations.
Second, we examined the top-scoring site pairs, and compared them with known SDRs from a mutagenesis study  in which ten sites of the ERBB2IP-1 domain were mutated and the corresponding changes of peptide specificity reported. This comparison provides direct evaluation of our SDR identification procedure on the subset of sites that were tested in the assay.
3.1.2 Synthetic PDZ domains
In a recent study, the mutagenesis study in Tonikian et al.  was extended. A large amount of mutations were introduced at the ten sites, resulting in 61 variations of the Erbin domain that are functional in recognizing some C-terminal heptapeptides . As with the natural PDZ domains, we compared the uncertainty coefficients with the physical distances in the 2H2C PDB structure. Since the synthetic PDZ domains are 100% conserved at sites other than the ten selected ones, and have a specific set of mutations at the ten sites introduced by the mutagenesis experiments, their MSA exhibits some statistical properties different from those of the natural PDZ domains.
3.1.3 SH3 domains
We obtained 23 yeast SH3 domains and the corresponding PWMs of the bound peptides from phage display experiments from a recent study . We aligned the PRDs based on a published structural alignment , and aligned the peptide PWMs based on both the general PxxP pattern and some published alignments [15, 56]. The pairwise sequence identity ranges from 0.07 to 0.79, with an average of 0.24.
We applied the same prediction and evaluation procedures as in the case of PDZ, except that in this case we did not have large-scale mutagenesis data, and therefore the prediction results were only evaluated against the physical distances calculated from the crystal structure 1N5Z in PDB, which contains the yeast Pex13 SH3 domain bound to a Pex14 peptide , and the findings of some previous studies.
3.1.4 Kinase domains
We also obtained 149 serine/threonine protein kinase domains from four species (S. cerevisiae, H. sapiens, S. pombe and D. discoideum) and the PWMs of their corresponding bound peptides . The MSA was made using MUSCLE  followed by some manual corrections. The prediction results were evaluated against distances calculated from the crystal structure 1ATP of mouse catalytic subunit of cAMP-dependent protein kinase complexed with Mn-ATP and a peptide inhibitor  in PDB, and some findings in previous studies. The pairwise sequence identity ranges from 0.09 to 0.92, with an average of 0.23.
3.2 Covariation score correlates with physical proximity and reconfirms previous findings
The covariation score between two sites is found to correlate negatively with the physical distance between them, regardless of the exact definition of the distance measure [see Additional file 1 Figure S1, Additional file 2 Figure S2 and Additional file 3 Figure S3 for the results] when the distance between residue centers, alpha carbon atoms and closest atoms minus their van der Waals' radii were used, respectively. All P-values were computed using Fisher transformation . For PDZ, we have also compared the correlations based on several other PDZ structures, and observed similar patterns [Additional file 4 Figure S4].
Site pairs with the highest covariation scores.
Domain family Ref. PDB Structure rank
It is also known that the residue corresponding to Glu31 in the RT loop of SH3 domains is a major determinant of the identity of the P-3 residue of the ligand [64, 65]. Since the P-3 residue does not exist in the 1N5Z structure, it is not included in the correlation plots. However, when we checked the covariation scores, indeed the ligand residue having the highest score with Glu31 is the P-3 residue. This observation illustrates the potential of our method to identify SDRs when structural information is not available.
We found that the pair between Tyr229 and position +1, besides being the top-scoring pair when uncertainty coefficient was used as the covariation score, was also consistently one of the highest-scoring pairs when covariation was measured by other normalized forms of mutual information. These consistent results made us hypothesize that Tyr229 is also involved in determining binding specificity of the kinase domain, and has long-range coupling with position +1 of the bound peptide. In a previous study, this residue was predicted to be involved in linking nucleotide binding and peptide binding in protein kinases . Interestingly, in the study Tyr229 and Leu205 are predicted to belong to the same special network (termed the θ-shaped network) of related residues. It thus might be the case that Tyr229 acts through the residues in the network to affect the recognition of the +1 position of the peptide.
3.3 PDZ predictions are consistent with mutagenesis results
We further validated our predictions with the natural PDZ domains by using a mutagenesis dataset from a domain specificity study  as described in the Materials and Methods section.
In our covariation calculation, among the ten mutated sites, four were filtered as they were too conserved (Ile36 [β2-1], Ile38 [β2-3], His88 [α2-1] and Val92 [α2-5]). Interestingly, in the mutagenesis study, indeed no significant changes to the peptide PWM could be observed for Ile36 and Ile38. The high conservation of them is thus probably caused by a structural or functional role that is independent of peptide binding.
Validation results of our PDZ predictions.
PDZ site in 2H2C
Structure-based nomenclature 
The predicted pair between Phe34 and position -3 has a distance of 15.0 Å in the PDB structure 2H2C. If the SDRs of different class I PDZ domains are similar, this predicted pair is another example that suggests our covariation method could potentially identify physically distant SDR pairs.
3.4 Covariation scores improve prediction of bound peptide profiles
In general, the prediction error is lower with a smaller fraction of PRDs left out for testing. This is expected, as having more PRDs in the training set allows for more accurate computation of covariation scores and the construction of more informative prediction models.
In all cases, the weighted average method using covariation scores outperformed regression tree and the weighted average method using uniform scoring. This suggests that the covariation score provided a meaningful way to weight useful features (that is, PRD sites) for predicting residue distributions of the bound peptides. Interestingly, while the regression tree method also performed feature weighting, in general it performed worse than both weighted average methods. The low performance could be due to over-fitting, as the regression trees are rich in expressive power while the numbers of PRDs in the datasets are small.
We present a novel way to use underutilized data. Our method is a valuable tool for exploring the specificity space of PRDs. Moreover, as the amount of specificity data is increasing swiftly, also due to the advent of next-generation sequencing and its applications to phage display , our method will prove even more valuable to make optimal use of this kind of data.
We think our covariation approach can be used in conjunction with other methods to improve SDR predictions. Since most current approaches are based on force fields and structural methods, our method opens up a new perspective for improvement. As shown in the recent PRD specificity prediction challenge of the DREAM4 competition , most likely a combination of structural and statistical methods will be most successful at predicting specificities.
One limitation of our approach is that it does not consider possible relationships between different residue pairs. As multiple PRD residues could simultaneously interact with a peptide residue and multiple peptide residues could simultaneously interact with a PRD residue , binding specificity could be more accurately modeled by considering covariation signals between residue groups. Furthermore, since a residue could have an indirect covariation signal with another residue through an intermediate residue , performing residue group analysis could help filter out these non-SDR intermediates that have relatively high covariation signals.
Another limitation of our approach is that it fails to identity SDRs that are highly conserved. Indeed we have observed that in PDZ, some highly conserved residues (for example α2-1) are physically close to the peptide and have been experimentally shown to affect binding specificity when mutated  [Additional file 5 Figure S5]. On the other hand, some SDRs are not highly conserved, but exhibit strong covariation patterns with peptide residues (for example β3:α1-1). Future approaches could improve upon our current method by combining information about conservation with covariation to identity SDRs.
There are also PRD residues that determine binding but not binding specificity in that if they are mutated, the resulting effect on binding cannot be restored by a second mutation. For instance, if a residue is critical to the protein structure, mutating it could seriously affect the stability of the protein, which in turn affects peptide binding. These residues are likely to be very conserved, and thus would not be ranked high by our method.
A third limitation of our approach, and more generally of all covariation analysis methods based on a multiple sequence alignment, is the dependency on the alignment quality. Different alignments could give very different results, especially for alignments with many gaps. To cope with this issue, we have used a published alignment for SH3, and made some manual corrections to the PDZ and kinase alignments generated by computer programs. Future approaches should try to minimize the effect of alignment quality on the analysis results.
While we have attempted to predict peptide PWMs, it is also possible to predict interactions given a PRD and a peptide. This problem has recently been studied using some large-scale datasets [9, 52]. It would be interesting to study how the concept of covariation can be incorporated into these prediction methods.
We have presented a novel approach that utilizes an as of yet underused source of data. We have shown that the covariation scores are consistent with previous findings from both a large-scale study, and other individual experiments. In addition, we have identified a number of candidate SDRs in a ranked list for future experimental validation. In particular, with the top-scoring pairs from natural PDZ domains and kinase domains both verified in previous work, the SH3 top-scoring pairs are good candidates for testing their roles in determining the binding specificity of SH3 domains.
multiple sequence alignment
peptide recognition domains
position weight matrix
statistical coupling analysis
specificity determining residues
We thank Xiaodan Fan for helpful discussions and Nisa Dar for technical assistance. We acknowledge support from the Natural Science and Engineering Research Council, the Ontario Research Fund, the Connaught Foundation, the NIH, the AL Williams Professorship funds, and the Yale University Biomedical High Performance Computing Center.
- Pawson T, Nash P: Assembly of cell regulatory systems through protein interaction domains. Science. 2003, 300 (5618): 445-452. 10.1126/science.1083653.View ArticlePubMedGoogle Scholar
- Pawson T, Linding R: Network medicine. FEBS Lett. 2008, 582: 1266-1270. 10.1016/j.febslet.2008.02.011.View ArticlePubMedGoogle Scholar
- Alto NM, Shao F, Lazar CS, Brost RL, Chua G, Mattoo S, McMahon SA, Ghosh P, Hughes TR, Boone C, Dixon JE: Identification of a bacterial type III effector family with G protein mimicry functions. Cell. 2006, 124: 133-145. 10.1016/j.cell.2005.10.031.View ArticlePubMedGoogle Scholar
- Doorbar J: Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci. 2006, 110: 525-541.View ArticlePubMedGoogle Scholar
- Carducci M, Licata L, Peluso D, Castagnoli L, Cesareni G: Enriching the viral-host interactomes with interactions mediated by SH3 domains. Amino Acids. 2010, 38 (5): 1541-1547. 10.1007/s00726-009-0375-z.View ArticlePubMedGoogle Scholar
- Lam HYK, Kim PM, Mok J, Tonikian R, Sidhu SS, Turk BE, Snyder M, Gerstein MB: MOTIPS: automated motif analysis for predicting targets of modular protein domains. BMC Bioinformatics. 2010, 11: 243-10.1186/1471-2105-11-243.PubMed CentralView ArticlePubMedGoogle Scholar
- Tonikian R, Zhang Y, Boone C, Sachdev SS: Identifying specificity profiles for peptide recognition modules from phage-displayed peptide libraries. Nat Protocols. 2007, 2 (6): 1368-1386. 10.1038/nprot.2007.151.View ArticlePubMedGoogle Scholar
- Landgraf C, Panni S, Montecchi-Palazzi L, Castagnoli L, Schneider-Mergener J, Volkmer-Engert R, Cesareni G: Protein interaction networks by proteome peptide scanning. PLoS Biol. 2004, 2: e14-10.1371/journal.pbio.0020014.PubMed CentralView ArticlePubMedGoogle Scholar
- Stiffler MA, Chen JR, Grantcharova VP, Lei Y, Fuchs D, Allen JE, Zaslavskaia LA, MacBeath G: PDZ domain binding selectivity is optimized across the mouse proteome. Science. 2007, 317 (5836): 364-369. 10.1126/science.1144592.PubMed CentralView ArticlePubMedGoogle Scholar
- Kaushansky A, Allen JE, Gordus A, Stiffler MA, Karp ES, Chang BH, MacBeath G: Quantifying protein-protein interactions in high throughput using protein domain microarrays. Nat Protocols. 2010, 5 (4): 773-790. 10.1038/nprot.2010.36.View ArticlePubMedGoogle Scholar
- Hutti JE, Jarrell ET, Chang JD, Abbott DW, Storz P, Toker A, Cantley LC, Turk BE: A rapid method for determining protein kinase phosphorylation specificity. Nat Methods. 2004, 1: 27-29. 10.1038/nmeth708.View ArticlePubMedGoogle Scholar
- Li L, Shakhnovich EI, Mirny LA: Amino acids determining enzyme-substrate specificity in prokaryotic and eukaryotic protein kinases. Proc Natl Acad Sci USA. 2003, 100 (8): 4463-4468. 10.1073/pnas.0737647100.PubMed CentralView ArticlePubMedGoogle Scholar
- Tonikian R, Zhang Y, Sazinsky SL, Currell B, Yeh JH, Reva B, Held HA, Appleton BA, Evangelista M, Wu Y, Xin X, Chan AC, Seshagiri S, Lasky LA, Sander C, Boone C, Bader GD, Sidhu SS: A specificity map for the PDZ domain family. PLoS Biol. 2008, 6: e239-10.1371/journal.pbio.0060239.PubMed CentralView ArticlePubMedGoogle Scholar
- Mok J, Kim PM, Lam HYK, Piccirillo S, Zhou X, Jeschke GR, Sheridan DL, Parker SA, Desai V, Jwa M, Cameroni E, Niu H, Good M, Remenyi A, Ma JLN, Sheu YJ, Sassi HE, Sopko R, Chan CSM, Virgilio CD, Hollingsworth NM, Lim WA, Stern DF, Stillman B, Andrews BJ, Gerstein MB, Snyder M, Turk BE: Deciphering protein kinase specificity through large-scale analysis of yeast phosphorylation site motifs. Sci Signal. 2010, 3: ra12-10.1126/scisignal.2000482.PubMed CentralView ArticlePubMedGoogle Scholar
- Cesareni G, Panni S, Nardelli G, Castagnoli L: Can we infer peptide recognition specificity mediated by SH3 domains?. FEBS Lett. 2002, 513: 38-44. 10.1016/S0014-5793(01)03307-5.View ArticlePubMedGoogle Scholar
- Beuming T, Farid R, Sherman W: High-energy water sites determine peptide binding affinity and specificity of PDZ domains. Protein Sci. 2009, 18: 1609-1619. 10.1002/pro.177.PubMed CentralView ArticlePubMedGoogle Scholar
- Lichtarge O, Bourne HR, Cohen FE: An evolutionary trace method defines binding surfaces common to protein families. J Mol Biol. 1996, 257: 342-358. 10.1006/jmbi.1996.0167.View ArticlePubMedGoogle Scholar
- Göbel U, Sander C, Schneider R, Valencia A: Correlated mutations and residue contacts in proteins. Proteins: Structure, Function, and Bioinformatics. 1994, 18: 309-317. 10.1002/prot.340180402.View ArticleGoogle Scholar
- Shindyalov IN, Kolchanov NA, Sander C: Can three-dimensional contacts in protein structures be predicted by analysis of correlated mutations?. Protein Eng. 1994, 7 (3): 349-358. 10.1093/protein/7.3.349.View ArticlePubMedGoogle Scholar
- Lockless SW, Ranganathan R: Evolutionarily conserved pathways of energetic connectivity in protein families. Science. 1999, 286 (5438): 295-299. 10.1126/science.286.5438.295.View ArticlePubMedGoogle Scholar
- Goh CS, Bogan AA, Joachimiak M, Walther D, Cohen FE: Co-evolution of proteins with their interaction partners. J Mol Biol. 2000, 299: 283-293. 10.1006/jmbi.2000.3732.View ArticlePubMedGoogle Scholar
- Pazos F, Valencia A: In silico two-hybrid system for the selection of physically interacting protein pairs. Proteins: Structure, Function, and Bioinformatics. 2002, 47: 219-227. 10.1002/prot.10074.View ArticleGoogle Scholar
- Ramani AK, Marcotte EM: Exploiting the co-evolution of interacting proteins to discover interaction specificity. J Mol Biol. 2003, 327: 273-284. 10.1016/S0022-2836(03)00114-1.View ArticlePubMedGoogle Scholar
- Pazos F, Ranea JAG, Juan D, Sternberg MJE: Assessing protein co-evolution in the context of the tree of life assists in the prediction of the interactome. J Mol Biol. 2005, 352 (4): 1002-1015. 10.1016/j.jmb.2005.07.005.View ArticlePubMedGoogle Scholar
- Tiller ERM, Biro L, Li G, Tillo D: Codep: maximizing co-evolutionary interdependencies to disvoer interacting proteins. Proteins: Structure, Function, and Bioinformatics. 2006, 63 (4): 822-831. 10.1002/prot.20948.View ArticleGoogle Scholar
- Socolich M, Lockless SW, Russ WP, Lee H, Gardner KH, Ranganathan R: Evolutionary information for specifying a protein fold. Nature. 2005, 437 (7058): 512-518. 10.1038/nature03991.View ArticlePubMedGoogle Scholar
- Gloor GB, Martin LC, Wahl LM, Dunn SD: Mutual information in protein multiple sequence alignments reveals two classes of coevolving positions. Biochemistry. 2005, 44 (19): 7156-7165. 10.1021/bi050293e.View ArticlePubMedGoogle Scholar
- Fuchs A, Martin-Galiano AJ, Kalman M, Fleishman S, Ben-Tal N, Frishman D: Co-evolving residues in membrane proteins. Bioinformatics. 2007, 23 (24): 3312-3319. 10.1093/bioinformatics/btm515.View ArticlePubMedGoogle Scholar
- Halperin I, Wolfson H, Nussinov R: Correlated mutations: advances and limitations. A study on fusion proteins and on the Cohesin-Dockerin families. Proteins: Structure, Function, and Bioinformatics. 2006, 63: 832-845. 10.1002/prot.20933.View ArticleGoogle Scholar
- Pazos F, Helmer-Citterich M, Ausiello G, Valencia A: Correlated mutations contain information about protein-protein interaction. J Mol Biol. 1997, 271: 511-523. 10.1006/jmbi.1997.1198.View ArticlePubMedGoogle Scholar
- Shulman AI, Larson C, Mangelsdorf DJ, Ranganathan R: Structural determinants of allosteric ligand activation in RXR heterodimers. Cell. 2004, 116: 417-429. 10.1016/S0092-8674(04)00119-9.View ArticlePubMedGoogle Scholar
- Pollock DD, Taylor WR, Goldman N: Coevolving protein residues: maximum likelihood identification and relationship to structure. J Mol Biol. 1999, 287: 187-198. 10.1006/jmbi.1998.2601.View ArticlePubMedGoogle Scholar
- Dekker JP, Fodor A, Aldrich RW, Yellen G: A perturbation-based method for calculating explicit likelihood of evolutionary co-variance in multiple sequence alignments. Bioinformatics. 2004, 20 (10): 1565-1572. 10.1093/bioinformatics/bth128.View ArticlePubMedGoogle Scholar
- Martin LC, Gloor GB, Dunn SD, Wahl LM: Using information theory to search for co-evolving residues in proteins. Bioinformatics. 2005, 21 (22): 4116-4124. 10.1093/bioinformatics/bti671.View ArticlePubMedGoogle Scholar
- Larson SM, Nardo AAD, Davidson AR: Analysis of covariation in an SH3 domain sequence alignment: applications in tertiary contact prediction and the design of compensating hydrophobic core substitutions. J Mol Biol. 2000, 303: 433-4446. 10.1006/jmbi.2000.4146.View ArticlePubMedGoogle Scholar
- Galitsky B: Revealing the set of mutually correlated positions for the protein families of immunoglobulin fold. In Silico Biol. 2003, 3 (0022):
- Dimmic MW, Hubisz MJ, Bustamante CD, Nielsen R: Detecting coevolving amino acid sites using Bayesian mutational mapping. Bioinformatics. 2005, 21 (Suppl. 1): i126-i135.View ArticlePubMedGoogle Scholar
- Tonikian R, Xin X, Toret CP, Gfeller D, Landgraf C, Panni S, Paoluzi S, Castagnoli L, Currell B, Seshagiri S, Yu H, Winsor B, Vidal M, Gerstein MB, Bader GD, Volkmer R, Cesareni G, Drubin DG, Kim PM, Sidhu SS, Boone C: Bayesian modeling of the yeast SH3 domain interactome predicts spatiotemporal dynamics of endocytosis proteins. PLoS Biol. 2009, 7: 21000218-View ArticleGoogle Scholar
- Yip KY, Patel P, Kim PM, Engelman DM, McDermott D, Gerstein M: An integrated system for studying residue coevolution in proteins. Bioinformatics. 2008, 24 (2): 290-292. 10.1093/bioinformatics/btm584.View ArticlePubMedGoogle Scholar
- Halabi N, Rivoire O, Leibler S, Ranganathan R: Protein sectors: evolutionary units of three-dimensional structure. Cell. 2009, 138: 774-786. 10.1016/j.cell.2009.07.038.PubMed CentralView ArticlePubMedGoogle Scholar
- Weigt M, White RA, Szurmant H, Hoch JA, Hwa T: Identification of direct residue contacts in protein-protein interaction by message passing. Proc Natl Acad Sci USA. 2009, 106: 67-72. 10.1073/pnas.0805923106.PubMed CentralView ArticlePubMedGoogle Scholar
- Burger L, van Nimwegen E: Disentangling direct from indirect co-evolution of residues in protein alignments. PLoS Comput Biol. 2010, 6: e1000633-10.1371/journal.pcbi.1000633.PubMed CentralView ArticlePubMedGoogle Scholar
- Cover TM, Thomas JA: Elements of Information Theory. 2006, New York: Wiley-Interscience, 2Google Scholar
- Gerstein M, Sonnhammer ELL, Chothia C: Volume changes in protein evolution. J Mol Biol. 1994, 236: 1067-1078. 10.1016/0022-2836(94)90012-4.View ArticlePubMedGoogle Scholar
- Press WH, Flannery BP, Teukolsky SA, Vetterling WT: Numerical Recipes: The Art of Scientific Computing. 1986, Cambridge: Cambridge University PressGoogle Scholar
- Goebel B, Dawy Z, Hagenauer J, Mueller JC: An approximation to the distribution of finite sample size mutual information estimates. Proceedings of IEEE International Conference on Communications (ICC'05), Volume 2. 2005, 1102-1106.Google Scholar
- Aktulga HM, Kontoyiannis I, Lyznik LA, Szpankowski L, Grama AY, Szpankowski W: Identifying statistical dependence in genomic sequence via mutual information estimates. EURASIP J Bioinformatics Syst Biol. 2007, 2007: 14741-Google Scholar
- Pirovano W, Feenstra KA, Heringa J: Sequence comparison by sequence harmony identifies subtype-specific functional sites. Nucleic Acids Res. 2006, 34 (22): 6540-6548. 10.1093/nar/gkl901.PubMed CentralView ArticlePubMedGoogle Scholar
- Hall M, Frank E, Holmes G, Pfahringer B, Reutemann P, Witten IH: The WEKA data mining software: an update. SIGKDD Explorations. 2009, 11: 10-18. 10.1145/1656274.1656278.View ArticleGoogle Scholar
- Thompson JD, Higgins DG, Gibson TJ: CLUSTAL W: improving the sensitivity of progressive multiple sequence alignmnet through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 1994, 22 (22): 4673-4680. 10.1093/nar/22.22.4673.PubMed CentralView ArticlePubMedGoogle Scholar
- Cock PJA, Antao T, Chang JT, Chapman BA, Cox CJ, Dalke A, Friedberg I, Hamelryck T, Kau F, Wilczynski B, de Hoon MJL: Biopython: freely available python tools for computational molecular biology and bioinformatics. Bioinformatics. 2009, 25 (11): 1422-1423. 10.1093/bioinformatics/btp163.PubMed CentralView ArticlePubMedGoogle Scholar
- Chen JR, Chang BH, Allen JE, Stiffler MA, MacBeath G: Predicting PDZ domain-peptide interactions from primary sequences. Nat Biotechnol. 2008, 26 (9): 1041-1045. 10.1038/nbt.1489.PubMed CentralView ArticlePubMedGoogle Scholar
- Appleton BA, Zhang Y, Wu P, Yin JP, Hunziker W, Skelton NJ, Sidhu SS, Wiesmann C: Comparative structural analysis of the Erbin PDZ domain and the first PDZ domain of ZO-1. Insights into determinants of PDZ domain specificity. J Biol Chem. 2006, 281 (31): 22312-22320. 10.1074/jbc.M602901200.View ArticlePubMedGoogle Scholar
- Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The protein data bank. Nucleic Acids Res. 2000, 28:Google Scholar
- Ernst A, Sazinsky SL, Hui S, Currell B, Dharsee M, Seshagiri S, Bader GD, Sidhu SS: Rapid evolution of functional complexity in a domain family. Sci Signal. 2009, 2: ra40-10.1126/scisignal.2000350.View ArticleGoogle Scholar
- Tong AHY, Drees B, Nardelli G, Bader GD, Brannetti B, Castagnoli L, Evangelista M, Ferracuti S, Nelson B, Paoluzi S, Quondam M, Zucconi A, Hogue CWV, Fields S, Boone C, Cesareni G: A combined experimental and computational strategy to define protein interaction networks for peptide recognition modules. Science. 2002, 295 (5553): 321-324. 10.1126/science.1064987.View ArticlePubMedGoogle Scholar
- Douangamath A, Filipp FV, Klein AT, Barnett P, Zou P, Voorn-Brouwer T, Vega M, Mayans OM, Sattler M, Distel B, Wilmanns M: Topography for independent binding of α-helical and PPII-helical ligands to a peroxisomal SH3 domain. Mol Cell. 2002, 10: 1007-1017. 10.1016/S1097-2765(02)00749-9.View ArticlePubMedGoogle Scholar
- Edgar RC: MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res. 2004, 32 (5): 1792-1797. 10.1093/nar/gkh340.PubMed CentralView ArticlePubMedGoogle Scholar
- Zheng J, Trafny EA, Knighton DR, Xuong NH, Taylor SS, Eyck LFT, Sowadski JM: A refined crystal structure of the catalytic subunit of cAMP-dependent protein kinase complexed with MnATP and a peptide inhibitor. Acta Crystallogr D. 1993, 49: 362-365. 10.1107/S0907444993000423.View ArticlePubMedGoogle Scholar
- Fisher RA: On the 'probable error' of a coefficient of correlation deduced from a small sample. Metron. 1921, 1: 3-32.Google Scholar
- Humphrey W, Dalke A, Schulten K: VMD: visual molecular dynamics. J Mol Graph. 1996, 14: 33-38. 10.1016/0263-7855(96)00018-5.View ArticlePubMedGoogle Scholar
- Im YJ, Lee JH, Park SH, Park SJ, Rho SH, Kang GB, Kim E, Eom SH: Crystal structure of the Shank PDZ-ligand complex reveals a class I PDZ interaction and a novel PDZ-PDZ dimerization. J Biol Chem. 2003, 278 (48): 48099-48104. 10.1074/jbc.M306919200.View ArticlePubMedGoogle Scholar
- Espanel X, Sudol M: Yes-associated protein and p53-binding protein-2 interact through their WW and SH3 domains. J Biol Chem. 2001, 276 (17): 14514-14523.PubMedGoogle Scholar
- Musacchio A, Saraste M, Wilmanns M: High-resolution crystal structures of tyrosine kinase SH3 domains complexed with proline-rich peptides. Nat Struct Mol Biol. 1994, 1 (8): 546-551. 10.1038/nsb0894-546.View ArticleGoogle Scholar
- Yu H, Chen JK, Feng S, Dalgarno DC, Brauer AW, Schrelber SL: Structural basis for the binding of proline-rich peptides to SH3 domains. Cell. 1994, 76: 933-945. 10.1016/0092-8674(94)90367-0.View ArticlePubMedGoogle Scholar
- Smith CM, Radzio-Andzelm E, Akamine P, Taylor SS: The catalytic subunit of cAMP-dependent protein kinase: prototype for an extended network of communication. Prog Biophys Mol Biol. 1999, 71: 313-341. 10.1016/S0079-6107(98)00059-5.View ArticlePubMedGoogle Scholar
- Johnson DA, Akamine P, Radzio-Andzelm E, Taylor SS: Dynamics of cAMP-dependent protein kinase. Chem Rev. 2001, 101 (8): 2243-2270. 10.1021/cr000226k.View ArticlePubMedGoogle Scholar
- Xu F, Du P, Shen H, Hu H, Wu Q, Xie J, Yu L: Correlated mutation analysis on the catalytic domains of serine/threonine protein kinases. PLoS One. 2009, 4: e5913-10.1371/journal.pone.0005913.PubMed CentralView ArticlePubMedGoogle Scholar
- Gfeller D, Butty F, Wierzbicka M, Verschueren E, Vanhee P, Huang H, Ernst A, Dar N, Stagljar I, Serrano L, Sidhu SS, Bader GD, Kim PM: The multiple-specificity landscape of modular peptide recognition domains. Mol Syst Biol. 2011, 7: 484-PubMed CentralView ArticlePubMedGoogle Scholar
- DREAM4, Challenge 1: Peptide Recognition Domain (PRD) Specificity Prediction. 2009, [http://wiki.c2b2.columbia.edu/dream/index.php/D4c1]
- London N, Movshovitz-Attias D, Schueler-Furman O: The structural basis of peptide-protein binding strategies. Structure. 2010, 18: 188-199. 10.1016/j.str.2009.11.012.View ArticlePubMedGoogle Scholar
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