The plastic landscape of repeat proteins

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.