Evolution of the b-propeller fold

Repetition is a widespread feature of natural proteins. The repeated units vary considerably in size, from single residues to entire domains. Repeats that fold into single domains yield a hierarchy of structural complexity, from fibrous domains made by the repetition of patterns only a few amino acids long (collagen, coiled coils, b-helices), to solenoid domains formed by the repetition of simple supersecondary structures (aa-hairpins: tetratricopeptide and HEAT repeats; bb-hairpins: choline-binding domains; ba-hairpins: leucine-rich repeats), to globular domains formed by the repetition, frequently in interleaved form, of complex supersecondary structure units (bbab: cradle-loop barrels; bab: ferredoxins). Toroids are intermediate in complexity between solenoids and globular proteins, as they are usually formed by simple, noninterleaved supersecondary structure units, but fold into a closed, rather than open structure (aa-hairpins: protein prenyltransferases; bb-hairpins: porins; ba-hairpins: TIM barrels). b-Propellers are circular folds with 4–8 repeats. This variability is unusual among toroids, which are generally formed by a specific number of repeats, differing in special cases by at most one unit (as, e.g., in the six-hairpin versus seven-hairpin glycosidases). From an evolutionary point of view, b-propellers are also remarkable as their degree of internal sequence symmetry ranges over the full evolutionary spectrum, from binding proteins with nearly identical repeats to fully differentiated enzymes whose origin from repetition can only be seen in their structures. The repeated unit is a four-stranded b-meander, whose strands are labeled A to D from Nto C-terminus. The meanders are arranged radially and in slightly tilted fashion around a central pore, with strand A innermost. They resemble the blades of a propeller, hence the name of the structure. Although their detailed interaction varies somewhat between propellers with different numbers of blades, the blades themselves are structurally very similar, irrespective of the size of the propeller from which they originate, and their inner three b-strands can generally be superimposed with an RMSD of less than 1 Å (Fig. 1). The central pore they enclose is funnel-shaped rather than cylindrical, with the narrow end often being the binding site for ions or substrates. In many b-propellers, up to three strands of the last blade are circularly permuted to the N-terminus of the protein. This places the termini of the protein into adjacent, hydrogen-bonded strands (‘‘velcro’’ closure), instead of between blades, and presumably confers additional structural stability to the propeller. Some propellers also have N-terminal extensions that add a fifth strand to the first blade.