From Protein Structure to Function with Bioinformatics.pdf

6 Function Diversity Within Folds and Superfamilies 149annotate that protein with function X. But in practise, the situation is more complexbecause a functionally diverse fold can misleadingly appear to be related toonly one function due to sampling bias.In any case, there are documented cases where fold identification has helpedpredicting the function of a protein (Moult and Melamud 2000). For example, thethree-dimensional structure of the ycaC gene product from Escherichia colirevealed a fold similar to that adopted by a family of amidohydrolases, and furtherinvestigation indicated that this protein had a similar catalytic apparatus as otherproteins sharing that fold (Colovos et al. 1998; Moult and Melamud 2000).Increasing numbers of successful examples of function prediction via fold identificationare being documented in the context of structural genomics that globally aimat solving large numbers of protein structures (Adams et al. 2007). In most cases,however, successful function prediction does not result from fold identificationonly, but rather from a combination of fold relationship with other evidence such assequence motif recognition or functional site similarities.6.2.2.2 SupersitesGenerally, three-dimensional structures are very helpful for identifying proteinfunctional sites, i.e. the subsets of residues that are crucial for the molecular functionof the protein. Functional sites mostly consist of binding sites (sets of proteinresidues that interact with ligands) (Dessailly et al. 2008) or catalytic sites (sets ofresidues that directly participate in an enzymatic reaction) (Porter et al. 2004).One reason why structures are useful for detecting functional site(s) is that thelatter tend to occupy well-conserved topological locations in the structure.Furthermore, even when no definitive evidence supports homology between proteinsthat share a given fold, functional sites still tend to locate in similar regions of thethree-dimensional structures. Such functional sites are called supersites and havebeen shown to occur in a large number of analogous folds (or superfolds, see Section6.2.3.1), that is folds shared by non-homologous proteins (Russell et al. 1998).Figure 6.1 describes a very well-known example of supersite: the catalytic site ofproteins adopting the (β/α) 8barrel fold, in which the catalytic residues invariablyoccur at the C-terminal ends of the β-strands in the central parallel β-sheet, althoughthe particular β-strands to which they belong may vary (Nagano et al. 2002).6.2.2.3 SuperfoldsFolds that are adopted by proteins from many different superfamilies, and thatgenerally display remarkable functional diversity, have been called “superfolds”(Orengo et al. 1994). Striking examples of such superfolds comprising proteinswith many different functions include the TIM-like (β/α) 8barrel fold which isadopted by proteins from more than 25 diverse superfamilies (Nagano et al.2002); and the Rossmann-fold, which is adopted by proteins from 114 CATH