Residue centrality, functionally important residues, and active site shape: analysis of enzyme and non-enzyme families - PubMed (original) (raw)

Residue centrality, functionally important residues, and active site shape: analysis of enzyme and non-enzyme families

Antonio del Sol et al. Protein Sci. 2006 Sep.

Abstract

The representation of protein structures as small-world networks facilitates the search for topological determinants, which may relate to functionally important residues. Here, we aimed to investigate the performance of residue centrality, viewed as a family fold characteristic, in identifying functionally important residues in protein families. Our study is based on 46 families, including 29 enzyme and 17 non-enzyme families. A total of 80% of these central positions corresponded to active site residues or residues in direct contact with these sites. For enzyme families, this percentage increased to 91%, while for non-enzyme families the percentage decreased substantially to 48%. A total of 70% of these central positions are located in catalytic sites in the enzyme families, 64% are in hetero-atom binding sites in those families binding hetero-atoms, and only 16% belong to protein-protein interfaces in families with protein-protein interaction data. These differences reflect the active site shape: enzyme active sites locate in surface clefts, hetero-atom binding residues are in deep cavities, while protein-protein interactions involve a more planar configuration. On the other hand, not all surface cavities or clefts are comprised of central residues. Thus, closeness centrality identifies functionally important residues in enzymes. While here we focus on binding sites, we expect to identify key residues for the integration and transmission of the information to the rest of the protein, reflecting the relationship between fold and function. Residue centrality is more conserved than the protein sequence, emphasizing the robustness of protein structures.

PubMed Disclaimer

Figures

Figure 1.

Figure 1.

Distribution over all protein families of the averaged correlation coefficients between the closeness _z_-score values for all of the aligned residues in all pairs of family members.

Figure 2.

Figure 2.

Fragment of the 1dx4 protein family alignment. The closeness _z_-score values are shown above each residue. The _z_-score values >2.0 in at least 70% of the members of the family are highlighted in red. These are the centrally conserved residues.

Figure 3.

Figure 3.

Sensitivity, specificity, true positive (TP), false positive (FP), and false negative (FN) values calculated for the centrally conserved predicted residues in all families, enzyme, and non-enzyme families.

Figure 4.

Figure 4.

Percentages of conserved central positions in all protein families located in different functional sites—catalytic, heteroatom binding, and protein–protein interaction binding. Circles below the histogram represent in each case the percentage of families with at least one conserved central residue.

Figure 5.

Figure 5.

(A) Representation of two views of the surface of the β-lactamase (PDB code1bsg). The deepest cavities are depicted in yellow, blue, brown, and purple. Residues from the catalytic site, located in the yellow cavity, are shown as green and red spots. (B) Mesh representation of the same protein. Residues in cyan, red, and yellow correspond to predicted centrally conserved amino acids. The residue in red is also part of the catalytic site. The remaining catalytic site residues are shown in green. Those amino acids in cyan are neighbors of the catalytic site residues. All of these residues are clustered around the same cavity (area colored in yellow).

Figure 6.

Figure 6.

(A) Representation of the PDZ domain (PDB code 1be9). The predicted centrally conserved residues, LEU379 and PHE325, are shown in red. Both amino acids are in contact with the ligand (depicted in yellow). Residue PHE325 has been experimentally determined to be energetically coupled with residue HIS372 (key residue responsible for ligand specificity) and is part of the intramolecular signaling pathway proposed by Lockless and Ranganathan (1999). The other residues forming this pathway, ALA347 and LEU353 (colored in blue), have been suggested to participate in the allosteric communications (Lockless and Ranganathan 1999) and are in direct contact with the Cdc42 binding site of the PDZ domain in the mPar-6B protein. The functional importance of this pathway has been largely confirmed by experimental mutagenesis (Ota and Agard 2005). (B) The structure of the HIV-1 protease homodimer (PDB code1kzk). Predicted central residues are shown in red.

Similar articles

Cited by

References

    1. Aloy P., Querol E., Aviles F.X., Sternberg M.J. 2001. Automated structure-based prediction of functional sites in proteins: Applications to assessing the validity of inheriting protein function from homology in genome annotation and to protein docking. J. Mol. Biol. 311 395–408. - PubMed
    1. Amitai G., Shemesh A., Sitbon E., Shklar M., Netanely D., Venger I., Pietrokovski S. 2004. Network analysis of protein structures identifies functional residues. J. Mol. Biol. 344 1135–1146. - PubMed
    1. Atilgan A.R., Akan P., Baysal C., Vendruscolo M., Dokholyan N.V., Paci E., Karplus M. 2004. Small-world communication of residues and significance for protein dynamics. Small-world view of the amino acids that play a key role in protein folding. Biophys. J. 86 85–91. - PubMed
    1. Bader G.D., Donaldson I., Wolting C., Ouellette B.F., Pawson T., Hogue C.W. 2001. BIND––The biomolecular interaction network database. Nucleic Acids Res. 29 242–245. - PMC - PubMed
    1. Berman H.M., Westbrook J., Feng Z., Gilliland G., Bhat T.N., Weissig H., Shindyalov I.N., Bourne P.E. 2000. The protein databank. Nucleic Acids Res. 28 235–242. - PMC - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources