Protein interactions and ligand binding: from protein subfamilies to functional specificity - PubMed (original) (raw)

Protein interactions and ligand binding: from protein subfamilies to functional specificity

Antonio Rausell et al. Proc Natl Acad Sci U S A. 2010.

Abstract

The divergence accumulated during the evolution of protein families translates into their internal organization as subfamilies, and it is directly reflected in the characteristic patterns of differentially conserved residues. These specifically conserved positions in protein subfamilies are known as "specificity determining positions" (SDPs). Previous studies have limited their analysis to the study of the relationship between these positions and ligand-binding specificity, demonstrating significant yet limited predictive capacity. We have systematically extended this observation to include the role of differential protein interactions in the segregation of protein subfamilies and explored in detail the structural distribution of SDPs at protein interfaces. Our results show the extensive influence of protein interactions in the evolution of protein families and the widespread association of SDPs with protein interfaces. The combined analysis of SDPs in interfaces and ligand-binding sites provides a more complete picture of the organization of protein families, constituting the necessary framework for a large scale analysis of the evolution of protein function.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

Correspondence between the different subfamilies, and the EC groups (Top) and specific interactors (Bottom) for each protein family represented in the ROC space, where the distribution of the families is shown as a bidimensional histogram. The size of the colored boxes in each bin of the ROC space represents the percentage of protein families they contain, whereas the number shows the actual percentage. For the sake of simplicity, percentage values are rounded to the nearest integer (so that they may not add up to 100).

Fig. 2.

Fig. 2.

Workflow implemented to simultaneously detect the protein subfamilies and those residues responsible for such segregation (SDPs). This process is depicted for the class III aminotransferase family (Pfam PF00202). The homodimeric structure of the human ornithine aminotransferase (PDB 1oat) bound to Pyridoxal-5’-phosphate (in red spheres) is represented. The two subunits of the complex are shown as brown cartoon representation and with a gray surface. SDPs are highlighted in a yellow/violet spacefill and with a green surface. The figure was generated with Pymol (pymol.sourceforge.com).

Fig. 3.

Fig. 3.

Percentage of SDPs in the functional regions (Top) compared to the corresponding percentage of protein residues in these functional regions (medium) in each Pfam family. The data are grouped according to the type of functional region detected in each family (Bottom), whereas the number of families in each category is shown in parentheses. Ligand-binding sites shown in blue, heterodimeric interfaces in green, homodimeric interface in red, and their combinations in yellow. The intrachain interfaces have been omitted for the sake of simplicity.

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