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We provide statistically reliable sequence evidence indicating that at least 12 of 23 SCOP (betaalpha)(8) (TIM) barrel superfamilies share a common origin. This includes all but one of the known and predicted TIM barrels found in central metabolism. The statistical evidence is complemented by an examination of the details of protein structure, with certain structural locations favouring catalytic residues even though the nature of their molecular function may change. The combined analysis of sequence, structure and function also enables us to propose a phylogeny of TIM barrels. Based on these data, we are able to examine differing theories of pathway and enzyme evolution, by mapping known TIM barrel folds to the pathways of central metabolism. The results favour widespread recruitment of enzymes between pathways, rather than a "backwards evolution" model, and support the idea that modern proteins may have arisen from common ancestors that bound key metabolites., (Copyright 2000 Academic Press.) more...

A strategy is presented for protein fold recognition from secondary structure assignments (alpha-helix and beta-strand). The method can detect similarities between protein folds in the absence of sequence similarity. Secondary structure mapping first identifies all possible matches (maps) between a query string of secondary structures and the secondary structures of protein domains of known three-dimensional structure. The maps are then passed through a series of structural filters to remove those that do not obey simple rules of protein structure. The surviving maps are ranked by scores from the alignment of predicted and experimental accessibilities. Searches made with secondary structure assignments for a test set of 11 fold-families put the correct sequence-dissimilar fold in the first rank 8/11 times. With cross-validated predictions of secondary structure this drops to 4/11 which compares favourably with the widely used THREADER program (1/11). The structural class is correctly predicted 10/11 times by the method in contrast to 5/11 for THREADER. The new technique obtains comparable accuracy in the alignment of amino acid residues and secondary structure elements. Searches are also performed with published secondary structure predictions for the von-Willebrand factor type A domain, the proteasome 20 S alpha subunit and the phosphotyrosine interaction domain. These searches demonstrate how the method can find the correct fold for a protein from a carefully constructed secondary structure prediction, multiple sequence alignment and distant restraints. Scans with experimentally determined secondary structures and accessibility, recognise the correct fold with high alignment accuracy (86% on secondary structures). This suggests that the accuracy of mapping will improve alongside any improvements in the prediction of secondary structure or accessibility. Application to NMR structure determination is also discussed. more...