Annabel E. Todd (1), Christine A. Orengo (1) and Janet M. Thornton (1,2)

1. Department of Biochemistry and Molecular Biology, University College London, Darwin Building, Gower Street, London WC1E 6BT, UK
2. Department of Crystallography, Birkbeck College, Malet Street, London, WC1E 7HX

The recent growth in protein sequence and structural databases has revealed the functional diversity of many protein superfamilies. An understanding of how such diversity has evolved through sequence and structural changes is essential for the accurate functional annotation of the large number of uncharacterised gene products identified in genome sequencing projects. Given the large number of genes in the human genome, but a comparatively small number of folds, extensive combination, mixing and modulation of existing folds has occurred during evolution to generate the multitude of functions necessary to sustain life. With the first working draft of the human genome complete, and the sequencing of other multi-cellular organisms underway, a grasp of these evolutionary processes is required if we are to benefit from this wealth of data.

We have analysed how functional changes are implemented by modulation of sequence and structure with reference to 31 diverse enzyme superfamilies, and thus provide an overview of the mechanisms by which functional diversity has evolved. This has involved extensive reading of the literature combined with analyses of our own. Functional variation occurs mostly in more distantly related proteins (<40%) and the structural data have been essential for understanding the molecular basis of observed functional differences. A large number of variations and peculiarities are observed, at the atomic level through to gross structural rearrangements. Using selected examples, we present the structural and functional attributes which are conserved within some superfamilies and those that differ, and what bearing, if any, these similarities and changes have on protein function. The implications these observations have on structural genomics projects will be discussed.