Coiled-coils: stability, specificity, and drug delivery potential

The coiled-coil is a ubiquitous protein folding and assembly motif made of α-helices wrapping around each other forming a supercoil. The sequences of coiled-coils are made of seven-residue repeats, called heptads, and thus are polymer-like. Due to its simplicity and regularity, the coiled-coil is the most extensively studied protein motif. In this review, results on coiled-coil stability and specificity from structural and biophysical studies are summarized. It is pointed out that the primary sequences of coiled-coils over specify the secondary structure but under specify the tertiary/quaternary structure. This leads to two unique features of coiled-coil structure: linkage between stability and specificity and decoupling of secondary and tertiary/quaternary structural specificity. This is followed by a discussion of the potential of coiled-coils as drug delivery vehicles, particularly the prospect in two-staged pretargeted delivery. Such potentials are intimately related to the unique structural features of coiled-coils. The aim of this review is to illustrate how knowledge on protein stability and specificity can be used in the de novo design of peptide-based drug delivery vehicles with well-defined structure and interaction features.