The plastic landscape of repeat proteins

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Abstract
Nearly 20% of the proteins encoded by the human genome contain multiple repeated units of 30–40 amino acids often occurring in tandem arrays referred to as repeat domains (1). In this issue of PNAS, Werbeck and Itzhaki (2) describe the equilibrium folding mechanism of the largest repeat domain ever studied, D34, a 426-residue fragment encompassing the last 12 ankyrin repeats of Ankyrin R. Although some repeats behave as “beads-on-a-string” and fold independently, it is now becoming clear that many do not (3). Often, repeating elements only fold in the context of similar repeats and form extended superhelical structures, stabilized only by interactions within repeats and adjacent neighbors. In contrast to three-dimensional globular proteins, there are no direct interactions between residues distant in sequence space (4). This near one-dimensionality has enormous consequences for the description of the energy landscapes, thermodynamics, and kinetics of repeat-containing proteins. Ankyrin-repeat proteins are found in all three phyla and are present in some 6% of eukaryotic protein sequences (1, 5). Sequence and structural alignments reveal that conserved amino acids form a folded scaffold with nonconserved amino acids located preferentially on the surface (6, 7). Several groups have successfully designed stable ankyrin repeats and thereby have established that the conserved residues play the primary role in folding stability (6–8). Mutation of conserved residues nearly always results in reduction of stability, whereas mutation of nonconserved surface residues usually has little effect (9–11). In line with this manifestation of “minimal frustration,” it has been shown that the marginally stable ankyrin-repeat domain of IκBα is stabilized by mutating residues to conform to the consensus (12). The high cooperativity of the folding of globular proteins resembles a phase transition and arises in part from interactions between residues distant in sequence space. Because ankyrin-repeat domains …