MOLECULAR MODELING INDICATES THAT HOMODIMERS FORM THE BASIS FOR INTERMEDIATE FILAMENT ASSEMBLY FROM HUMAN AND MOUSE EPIDERMAL KERATINS

Mammalian epidermal keratin molecules adopt rod-shaped conformations t hat aggregate to form cytoplasmic intermediate filaments. To investiga te these keratin conformations and the basis for their patterns of mol ecular association, graphical methods were developed to relate known a mino acid sequences to probable spacial configurations. The results su pport the predominantly alpha-helical conformation of keratin chains, interrupted by short non-alpha-helical linkages. However, it was found that many of the Linkages have amino acid sequences typical of beta-s trand conformations. Space-filling atomic models revealed that the bet a-strand sequences would permit the formation of 2-chain and 4-chain c ylindrical beta-helices, fully shielding the hydrophobic amino acid ch ains that alternate with hydrophilic residues in these sequences. Beca use of the locations of the beta-helical regions in human and mouse st ratum corneum keratin chains, only homodimers of the keratins could in teract efficiently to form 2-chain and 4-chain beta-helices. Tetramers having the directions and degrees of overlap of constituent dimers th at have been identified by previous investigators are also predicted h om the interactions of beta-helical motifs. Heterotetramers formed fro m dissimilar homodimers could combine, through additional beta-helical structures, to form higher oligomers having the dimensions seen in el ectron microscopic studies. Previous results from chemical crosslinkin g studies can be interpreted to support the concept of homodimers rath er than heterodimers as the basis for keratin filament assembly. (C) 1 995 Wiley-Liss, Inc.