From Protein Structure to Function with Bioinformatics.pdf

6 Function Diversity Within Folds and Superfamilies 1516.3 Function Diversity Between Homologous ProteinsIn general, detecting homology (superfamily relationship) is much more helpful forfunction prediction than structural similarity alone (fold relationship). In this section,the relation between function diversity and structural homology is examinedand it is shown that even when homology is identified, many obstacles remain whenattempting to transfer functional annotations from one protein to another.6.3.1 DefinitionsBefore explaining how function diverges within superfamilies, it is necessary todefine clearly what a superfamily is, and how it is used in practise. The term family,which is used throughout this section, is also introduced.6.3.1.1 General UnderstandingA superfamily is an ensemble of proteins that are thought to be evolutionarilyrelated. Superfamily relationships can be determined by sequence similarities,which are detected using either traditional sequence alignment methods or moresensitive HMM searches (Reid et al. 2007). In the absence of sequence similarity,remote homologies can also be uncovered from structure and/or functionsimilarities. But contrary to the situation with sequence similarity, there is nowidely accepted approach to assess whether a structural or functional similarityis statistically significant. Because of that, the cut-offs used to define superfamilyrelationships can be arbitrary and somewhat subjective. Today, severaldatabases such as CATH and SCOP have come up with standard and widelyaccepteddefinitions of what superfamilies are (see Section 6.3.1.2). But in all ofthese, some degree of subjectivity in the assignment of proteins to superfamiliesremain, as hinted by the facts that they still rely on manual validation for thisspecific process, and that incompatible assignments are made in the differentdatabases for a number of domains (Greene et al. 2007; Andreeva et al. 2008).It is worth noting that both CATH and SCOP now pre-classify new protein structuresusing automated protocols, but final assignment to superfamilies still ultimatelyinvolves manual processing.The concept of a family is vaguer. Nowadays, a family is commonly understoodas a sub-classification of homologous proteins according to some criteria. Forexample, a sequence family at a particular level of sequence similarity groupstogether all proteins that share at least that level of sequence similarity; a functionalfamily groups together homologues that have the same function; an orthologousfamily groups together orthologues; etc. Depending on the focus of the databases,the definition of a family will vary.