From Protein Structure to Function with Bioinformatics.pdf

160 B.H. Dessailly and C.A. OrengoA known example of functional changes between homologous enzymes that isrelated to changes in the environment is described in the literature for the “Twodinucleotide binding domains” flavoproteins, where diversification of functionacross the superfamily has resulted from the conscription of different proteinpartners acting as electron acceptors, via a conserved mode of protein-proteininteractions (Ojha et al. 2007).Enzyme – Non-enzymeA source of functional diversity in superfamilies that is not often discussed in theliterature is that arising from the loss/gain of catalytic capability between homologues.Indeed, the analysis of non-enzymatic proteins is not as straightforwardas that of enzymes, for which several annotation systems and analysis tools arenow well-established (e.g. EC, KEGG and CSA; see Section 6.1) (Table 6.1).Non-enzymatic proteins are nevertheless frequently found in so-called enzymaticfamilies. The processes by which a protein loses catalytic capabilities are fairlystraightforward as the mere loss of a single crucial catalytic residue by substitutionwill generally lead to a loss of the enzymatic activity (Todd et al. 2002). The superfamilyof HUP domains (CATH code 3.40.50.620) consists mostly of enzymes, butcontains a few isolated examples of proteins with no known catalytic activity. Forexample, subunits of electron transferring flavoproteins constitute a separate functionalfamily and display significant sequence, structure, and function alterationsfrom other members of the superfamily (Aravind et al. 2002). An example at anotherlevel within that superfamily is that of the cryptochrome DASH, a non-enzyme thatshows striking similarities with evolutionarily related DNA repair photolyases interms of DNA binding and redox-dependent function, but also major differencesnotably in the active site (Brudler et al. 2003). There are also examples of superfamiliesthat are largely dominated by non-enzymes, such as the Periplasmic-Binding-Protein like domains (CATH code 3.40.190.10) in which many distinctfunctional families are identified on the basis of the molecules to which they bind,or of their role in the context of the cell, e.g. transporters or surface receptors.Extreme Examples of Functionally Diverse SuperfamiliesFrom the above discussion on mechanistically diverse and specificity diversesuperfamilies, it appears that most superfamilies maintain some degree of functionalcommonality between members in spite of their divergence. This is to beexpected since superfamilies consist of evolutionarily related proteins by definition,and the rules of parsimony make it reasonable to assume that homologousproteins may retain at least some aspect of their function in the course of evolution.However, examples of superfamilies also exist in which such commonalitieshave not been uncovered yet. In the previously mentioned analysis of large anddiverse superfamilies by Todd et al., one superfamily – the Hexapeptide RepeatProteins – displayed neither commonalities in catalytic mechanism nor in substrateselectivity (Todd et al. 2001). Another example of superfamily for which anyfunctional similarity fails to emerge between members is that of the HUP-domains.