Complete Structure of an Epithelial Keratin Dimer: Implications for Intermediate Filament Assembly

• Published in: PloS one 2015-07, Vol.10 (7), p.e0132706-e0132706
• Main Authors: Bray, David J, Walsh, Tiffany R, Noro, Massimo G, Notman, Rebecca
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Analysis; Assembly; Chirality; Computational chemistry; Computer simulation; Cytoskeleton; Disulfides - chemistry; Elasticity; Filaments; Humans; Hydrogen Bonding; Intermediate Filaments - chemistry; Keratin; Keratin-1 - chemistry; Keratin-10 - chemistry; Molecular biology; Molecular dynamics; Molecular Dynamics Simulation; Molecular Sequence Data; Molecular structure; Nails (Anatomy); Protein Folding; Protein Multimerization; Protein Structure, Secondary; Protein Structure, Tertiary; Proteins; Sequence Alignment; Skin; Structural models; Structure-function relationships; Tails; Three dimensional models
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0132706

Keratins are cytoskeletal proteins that hierarchically arrange into filaments, starting with the dimer sub-unit. They are integral to the structural support of cells, in skin, hair and nails. In skin, keratin is thought to play a critical role in conferring the barrier properties and elasticity of skin. In general, the keratin dimer is broadly described by a tri-domain structure: a head, a central rod and a tail. As yet, no atomistic-scale picture of the entire dimer structure exists; this information is pivotal for establishing molecular-level connections between structure and function in intermediate filament proteins. The roles of the head and tail domains in facilitating keratin filament assembly and function remain as open questions. To address these, we report results of molecular dynamics simulations of the entire epithelial human K1/K10 keratin dimer. Our findings comprise: (1) the first three-dimensional structural models of the complete dimer unit, comprising of the head, rod and tail domains; (2) new insights into the chirality of the rod-domain twist gained from analysis of the full domain structure; (3) evidence for tri-subdomain partitioning in the head and tail domains; and, (4) identification of the residue characteristics that mediate non-covalent contact between the chains in the dimer. Our findings are immediately applicable to other epithelial keratins, such as K8/K18 and K5/K14, and to intermediate filament proteins in general.