Coiled-coil stutter and link segments in keratin and other intermediate filament molecules: a computer modeling study.

Structural discontinuities have previously been identified in four regions of the coiled-coil rod domain structure present in intermediate filament (IF) protein molecules. These include a point at which a phase shift occurs in the heptad periodicity characteristic of the sequence of polar and apolar residues in alpha-helical coiled-coils, and three links that lack a heptad substructure. We have studied these regions by computer-based molecular modeling and comparative sequence analysis and conclude that the phasing discontinuity can be accommodated without significant distortion of the overall double-helical chain conformation; the L2 link has a similar conformation in all different types of IF molecules, a favorable conformation being one in which the two strands wrap tightly around each other; the L12 links vary in length between different IF types but contain important sequence similarities suggestive of a partial beta structure; the L1 links show larger variations in length, a lower degree of similarity, and probably diverse structures. Variations in the overall charges of the different links suggest that ionic interactions may play a significant role in filament assembly. The results also have general significance for other alpha-fibrous proteins in which either the characteristic heptad phasing undergoes a discontinuity or where a short non-coiled-coil sequence occurs within a coiled-coil rod domain structure.