Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012;8(11):e1002794.
doi: 10.1371/journal.pcbi.1002794. Epub 2012 Nov 29.

Accurate prediction of the dynamical changes within the second PDZ domain of PTP1e

Elisa Cilia  1 , Geerten W Vuister, Tom Lenaerts
Affiliations

Accurate prediction of the dynamical changes within the second PDZ domain of PTP1e

Elisa Cilia et al. PLoS Comput Biol. 2012.

Abstract

Experimental NMR relaxation studies have shown that peptide binding induces dynamical changes at the side-chain level throughout the second PDZ domain of PTP1e, identifying as such the collection of residues involved in long-range communication. Even though different computational approaches have identified subsets of residues that were qualitatively comparable, no quantitative analysis of the accuracy of these predictions was thus far determined. Here, we show that our information theoretical method produces quantitatively better results with respect to the experimental data than some of these earlier methods. Moreover, it provides a global network perspective on the effect experienced by the different residues involved in the process. We also show that these predictions are consistent within both the human and mouse variants of this domain. Together, these results improve the understanding of intra-protein communication and allostery in PDZ domains, underlining at the same time the necessity of producing similar data sets for further validation of thses kinds of methods.

PubMed Disclaimer

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Predictions for methyl-group containing residues.
A) The matrix of dynamical changes (heat map) for the methyl-group bearing residues, corresponding to a sub-matrix of the matrix in Figure S1 in Text S1. The matrix shows the absolute ΔMI, normalized between 0 and 1, colored from blue (0) to red (1) according to the color scale reported on top. B) Predictions mapped on the crystal structure (PDB-ID: 3LNY). Different colors are used for the different experimentally identified domain regions . The red, blue and yellow residues correspond to the binding site (BS), the distal surface 1 (DS1), and the distal surface 2 (DS2) respectively. The residues in green are part of a newly identified distal region (DS3). I35 is highlighted in purple. The RA-GEF2 peptide is shown in stick representation. C) The predictions for the methyl-group containing residues highlighted in a sequence alignment of the two homologous domains (hPDZ2 and mPDZ2). The residues highlighted in red, blue and yellow correspond to the residues experimentally identified as affected by peptide binding in . Residues composing the DS3 are highlighted in green and I35 in purple. Other predicted residues are squared in black.
Figure 2
Figure 2. Network of short-range dynamical changes in hPDZ2.
A) Residues highlighted in green are predicted on the basis of the complete matrix of changes in MI (light green for the methyl-group bearing side-chains and dark green for the others). Red edges represent an increase in MI, while blue edges represent a decrease in MI. The thickness of the edges represents the magnitude of change. Peptide residues and their contacts with the domain residues are highlighted in orange and the links connecting the peptide residues with the structure are not weighted. Yellow-dotted line illustrates an example of a long-range dynamical effect between LEU87 and HIS71. The network visualization follows the organic layout as implemented in Cytoscape . B) The non-methyl bearing residues composing the continuous surface DS4, are highlighted in red on the ribbon structure of hPDZ2. C) The non-methyl bearing residues composing the continuous surface that links the two distal surfaces DS2 and DS4, are highlighted in red on the ribbon structure of hPDZ2.
Figure 3
Figure 3. Quality assessment of the different predictors.
A) ROC curves of the information theoretical approach considering either the dynamical changes in the methyl side-chain containing residues only (blue line) or dynamical changes for all the residue types (red line); the black square represents the performance of the Gerek and Ozkan predictor , the purple square represents the Kong and Karplus predictor performance; grey and green lines represent the performance of a predictor ranking residues according to their betweenness centrality in the network derived from physical contacts using, respectively, the apo and the bound crystal structures. The two encircled points t1 and t2 correspond to the best performing predictors. B) The same as A, yet without the alanine residues, which were needed in the previous case for a fair comparison with the other approaches. We plot again the ROC curves of our approach compared to the baseline predictors in this setting.
Figure 4
Figure 4. Changes in backbone flexibility as a result of peptide binding.
The variations are mapped on the hPDZ2 crystal structure (PDB-ID: 3LNY). The different colors highlight the level of significance of the change, determined by z-scores. The Venn's diagram represents the predictions of methyl-containing residues obtained by our information theoretical approach (side-chains), compared to those obtained by analyzing the backbone variations (backbone). The underlined residues are those obtained from the experimental results in .
Figure 5
Figure 5. Similarities and differences in the predicted networks of dynamical changes in hPDZ2 and mPDZ2.
Predictions related to the residues containing methyl-groups on the side-chain at threshold t1 = 0.023. The picture shows two different domain orientations. The first orientation faces the binding groove; the second one, obtained by rotating the first one about 90 degrees to the right, shows the binding groove left side. Methyl-group bearing residues predicted for both the domains are shown in white, while differences in the predictions are highlighted in yellow. Amino acid differences between hPDZ2 and mPDZ2 are highlighted in green on the structure (see also the alignment in Figure S6 in Text S1).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ponting CP, Phillips C, Davies KE, Blake DJ (1997) PDZ domains: targeting signalling molecules to sub-membranous sites. BioEssays 19: 469–479. - PubMed
    1. Bezprozvanny I, Maximov A (2001) PDZ domains: More than just a glue. Proceedings of the National Academy of Sciences of the United States of America 98: 787–789. - PMC - PubMed
    1. Fuentes EJ, Der CJ, Lee AL (2004) Ligand-dependent dynamics and intramolecular signaling in a PDZ domain. Journal of molecular biology 335: 1105–1115. - PubMed
    1. Gianni S, Walma T, Arcovito A, Calosci N, Bellelli A, et al. (2006) Demonstration of long-range interactions in a PDZ domain by NMR, kinetics, and protein engineering. Structure 14: 1801–1809. - PubMed
    1. Petit CM, Zhang J, Sapienza PJ, Fuentes EJ, Lee AL (2009) Hidden dynamic allostery in a PDZ domain. Proceedings of the National Academy of Sciences of the United States of America 106: 18249–18254. - PMC - PubMed

Publication types

Substances