From Protein Structure to Function with Bioinformatics.pdf

7 Predicting Protein Function from Surface Properties 1717.2.3 Surface ConservationThe pseudo-random process of divergent evolution means that the majority of residuesin proteins that have a conserved function will be conserved because they are essentialto either the structure, or function, of the protein. A residue conservation profile is generatedby analysing a multiple sequence alignment of a protein family, with a methodsuch as Scorecons (Valdar 2002), which is in turn mapped onto the protein atoms.Displaying this information (whilst giving no physical or chemical information) givesan indication of conserved regions on the protein surface. This information can be effectivewhen identifying a conserved binding or active site in a given protein family.Only a small proportion of the protein surface is usually functional. Only a fewresidues are essential for the catalysis in an active site. Even for functions that occupy arelatively large surface area, like protein-protein interfaces, only a small number of theresidues contribute significantly to the stability (see Section 7.5.2). These few “functionalresidues” are often well conserved in many of the evolutionarily related proteins thathave a similar role. Thus function can be inferred by comparison of the conservation ofsurface residues at the surface. The interpretation of conservation is often difficult, unlessthe proteins are clearly orthologues because protein mutations can occur that completelychange the function resulting in mixtures of paralogues and orthologues in the proteinfamily which is being analysed. Whilst there are ways to exclude paralogues from themultiple alignments (O’Brien et al. 2005), care must be taken when comparing sequenceswith 30% sequence identity as only half of binding sites are correctly predicted (Devosand Valencia 2000), but greater sequence similarity does not necessarily imply similarfunction (Todd et al. 2002). The TIM-barrel family of proteins demonstrate that the samefold can host a variety of different functions, as discussed in detail in Chapter 6.One problem is determining which of the conserved residues are the most functionallyimportant. The evolutionary trace method (Lichtarge et al. 1996) uses aphylogenetic tree to approximate the evolutionary process used to obtain the rangeof sequences that show some similarity to a query sequence. The hierarchical cladesare taken to represent groups of sequences with conserved function, where the mostspecific groups at the tips of the branches have the most specific functions. Residuesat a given position in the alignment that are conserved in all of the sequences of oneclade, but not in less specific clades are termed “evolutionary trace” residues. Theseresidues are the defining residues of the clade and can be considered essential to thefunction of the group of sequences. The ConSurf server (Pupko et al. 2002) uses amodification of the basic evolutionary trace procedure to colour a protein structureto better highlight the location of conserved residues on a protein surface.7.3 Function Predictions Using Surface PropertiesOne of the main goals of the structural genomics initiatives is to populate new foldspace, particularly in order to determine structures for proteins of unknown functionor of medical importance. In the case of those with no assigned function the