Structural features of keratin intermediate filaments.
The first step in the assembly of a keratin intermediate filament (KIF) is the formation of a type I/type II heterodimer molecule in which two chains become aligned in parallel and close axial registration to form a flexible segmented alpha-helical coiled-coil rope 46 nm long. The segments of coiled-coil are interspersed by sequences that introduce irregularities of unknown structure. Here we have modeled two of these, the link L2 and the heptad discontinuity located near the middle of segment 2B. In a model for L2, the orientation of the coiled-coil structure is turned through about 180 degrees over the eight residue stretch constituting this link segment. In contrast, the heptad discontinuity in segment 2B would seem to result in only minimal distortion of the coiled-coil rope, contrary to previous expectations. Little is known about how the neighboring molecules are aligned and packed within the assembled KIF. Crosslinking experiments with KIF have determined that two neighboring molecules are aligned anti-parallel and axially in three ways, and predict that similarly-directed molecules could be overlapped by about 1 nm. The two-dimensional surface lattice resulting from these data predicts an axial periodicity of 22.6 nm, which in fact is visible by electron microscopy of shadowed KIF. Interestingly, most of the amino acid substitutions resulting from mutations in the keratin genes found in genodermatoses are clustered in this molecular overlap region. Although we do not yet know how the rows of antiparallel molecules fold in three dimensions to form an intact KIF, certain of the observed crosslinks could also occur between nearest neighbor parallel molecules across a four-molecule strand; that is, KIF may be built from bundles or protofibrils. These insights on molecular structure and molecular packing provide new constraints on models for KIF structure.
Steinert
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PM
Skin Biology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892-2755.
North
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Parry
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D000595:Amino Acid Sequence; D000818:Animals; D008040:Genetic Linkage; D006801:Humans; D007382:Intermediate Filaments / Q000378:metabolism* / Q000648:ultrastructure*; D007633:Keratins / Q000235:genetics / Q000648:ultrastructure*; D008958:Models, Molecular; D008961:Models, Structural; D008969:Molecular Sequence Data; D005810:Multigene Family; D009154:Mutation; D012871:Skin Diseases / Q000235:genetics
D007633:Keratins