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Abstract

Due to the regularity of their interactions, coiled coils are frequently very stable proteins and many have been reported to withstand extreme chemical and thermal conditions, even when they comprise chains of little more than 30 residues. Given this thermodynamic stability, it may come as a surprise that coiled coils are close to the unfolded state; in fact, it is not uncommon for them to be mistaken for natively unstructured polypeptides by disorder prediction programs. This failure cuts both ways: highly charged sequences that are largely devoid of hydrophobic residues and lack sequence repeats indicative of coiled-coil structure are often predicted as coiled coils, even though they are most likely unstructured. We propose that coiled-coil sequences have evolved to resemble unstructured polypeptides because they need to ensure in-register folding of rods that are sometimes many hundreds of residues long. Since packing interactions are structurally the same all along the rod, coiled coils are confronted with many, essentially isoenergetic intermediates that could trap the folding chains out of register if they formed spontaneously. To prevent this, coiled coils have evolved sequences that allow them to be quite stable thermodynamically, once folded, but have kinetic folding barriers that maintain them in an unstructured state until folding has been initiated at a nucleation site and is therefore guaranteed to be in register. This nucleation site can be within the coiled coil (‘trigger sequence’), or in an adjacent domain (such as the foldon of T4 fibritin).