Common Evolutionary Origin of Swapped-Hairpin and Double-Psi β Barrels

The core of swapped-hairpin and double-psi β barrels is formed by duplication of a conserved βαβ element, suggesting a common evolutionary origin. The path connecting the two folds is unclear as the two barrels are not interconvertible by a simple topological modification, such as circular permutation. We have identified a protein family whose sequence properties are intermediate to the two folds. The structure of one of these proteins, Pyrococcus horikoshii PhS018, is also built by duplication of the conserved βαβ element but shows yet a third topology, which we name the RIFT barrel. This topology is widespread in the structure database and spans three folds of the SCOP classification, including the middle domain of EF-Tu and the N domain of F1-ATPase. We propose that swapped-hairpin β barrels arose from an ancestral RIFT barrel by strand invasion and double-psi β barrels by a strand swap. We group the three barrel types into a metafold, the cradle-loop barrels.