From Protein Structure to Function with Bioinformatics.pdf

162 B.H. Dessailly and C.A. Orengohen egg-white lysozyme and mammalian α-lactalbumin; see Section 6.3.3), andsometimes even between exactly identical proteins seen in diverse contexts.Typically, such proteins adopt entirely new functions as a consequence of theirrecruitment in a novel environment. A well-known example of such a protein is thatof duck eye lens crystallins, which are identical in sequence to liver enolase andlactate dehydrogenase (Piatigorsky et al. 1994; Whisstock and Lesk 2003). Severalsuch cases have been documented and are collectively referred to as “moonlightingproteins” (Jeffery 2003). Furthermore, increasing evidence indicate that enzymescarry in them the potential for functional changes, in that they are generally able tocatalyse promiscuous reactions in addition to the main, generally highly specific,reaction they are responsible for (Khersonsky et al. 2006). These extreme cases offunction diversity between proteins displaying no or very low differences insequence and structure are mentioned here in order to convey further the notion thatthe relationship between sequence, structure and function diversity is definitely ahighly complex one, and that simple and reliable rules to predict function fromsequence and structure are difficult to derive.6.4 ConclusionIn this chapter, the relationship between function and structural similarity has beenexplored. It was first shown that proteins sharing the same fold do not necessarilyshare the same function, but that knowledge of the structure and fold is often helpfulfor function annotation. The definition of a fold was discussed, with particularemphasis on the recent conceptual shift towards a continuous rather than discreteview of fold space.Proteins sharing the same fold are not necessarily homologous. On the contrary,superfamilies are defined as groups of evolutionarily related proteins. Buteven within superfamilies, proteins are likely to perform different functions.Diverse processes to explain the evolution of superfamilies, and of proteinfunction within them have been considered in the literature, and these processesare commented upon here. It is shown that even though evolutionarily relatedproteins do not necessarily share the same function, common elements of functionalityare generally likely to remain between them. For example, mechanisticallydiverse superfamilies consist of enzymes that share a common mechanisticattribute in the enzymatic reactions they catalyse.The relationship between protein function, structure and homology is complex,and perfect prediction of one of these attributes from any of the others is still notyet possible without errors. Nevertheless, identification of fold similarities orstructural homologies between proteins is clearly helpful in function prediction,and the increase in structure, sequence and function data from the various –omicsinitiatives promises to greatly improve our understanding of the relationshipsbetween these attributes.