Evolution of the β‐propeller fold

β‐Propellers are toroidal folds, in which repeated, four‐stranded β‐meanders are arranged in a circular and slightly tilted fashion, like the blades of a propeller. They are found in all domains of life, with a strong preponderance among eukaryotes. Propellers show considerable sequence diversity and are classified into six separate structural groups by the SCOP and CATH databases. Despite this diversity, they often show similarities across groups, not only in structure but also in sequence, raising the possibility of a common origin. In agreement with this hypothesis, most propellers group together in a cluster map of all‐β folds generated by sequence similarity, because of numerous pairwise matches, many of which are individually nonsignificant. In total, 45 of 60 propellers in the SCOP25 database, covering four SCOP folds, are clustered in this group and analysis with sensitive sequence comparison methods shows that they are similar at a level indicative of homology. Two mechanisms appear to contribute to the evolution of β‐propellers: amplification from single blades and subsequent functional differentiation. The observation of propellers with nearly identical blades in genomic sequences show that these mechanisms are still operating today. Proteins 2008. © 2007 Wiley‐Liss, Inc.