Modeling the self-organization property of keratin intermediate filaments. 2010

Jin Seob Kim, and Chang-Hun Lee, and Pierre A Coulombe
Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, USA. jskim@jhsph.edu

Keratin intermediate filaments (IFs) fulfill an important function of structural support in epithelial cells. The necessary mechanical attributes require that IFs be organized into a crosslinked network and accordingly, keratin IFs are typically organized into large bundles in surface epithelia. For IFs comprised of keratins 5 and 14 (K5, K14), found in basal keratinocytes of epidermis, bundling can be self-driven through interactions between K14's carboxy-terminal tail domain and two regions in the central α-helical rod domain of K5. Here, we exploit theoretical principles and computational modeling to investigate how such cis-acting determinants best promote IF crosslinking. We develop a simple model where keratin IFs are treated as rigid rods to apply Brownian dynamics simulation. Our findings suggest that long-range interactions between IFs are required to initiate the formation of bundlelike configurations, while tail domain-mediated binding events act to stabilize them. Our model explains the differences observed in the mechanical properties of wild-type versus disease-causing, defective IF networks. This effort extends the notion that the structural support function of keratin IFs necessitates a combination of intrinsic and extrinsic determinants, and makes specific predictions about the mechanisms involved in the formation of crosslinked keratin networks in vivo.

UI MeSH Term Description Entries
D007382 Intermediate Filaments Cytoplasmic filaments intermediate in diameter (about 10 nanometers) between the microfilaments and the microtubules. They may be composed of any of a number of different proteins and form a ring around the cell nucleus. Tonofilaments,Neurofilaments,Filament, Intermediate,Filaments, Intermediate,Intermediate Filament,Neurofilament,Tonofilament
D007633 Keratins A class of fibrous proteins or scleroproteins that represents the principal constituent of EPIDERMIS; HAIR; NAILS; horny tissues, and the organic matrix of tooth ENAMEL. Two major conformational groups have been characterized, alpha-keratin, whose peptide backbone forms a coiled-coil alpha helical structure consisting of TYPE I KERATIN and a TYPE II KERATIN, and beta-keratin, whose backbone forms a zigzag or pleated sheet structure. alpha-Keratins have been classified into at least 20 subtypes. In addition multiple isoforms of subtypes have been found which may be due to GENE DUPLICATION. Cytokeratin,Keratin Associated Protein,Keratin,Keratin-Associated Proteins,alpha-Keratin,Associated Protein, Keratin,Keratin Associated Proteins,Protein, Keratin Associated,alpha Keratin
D007700 Kinetics The rate dynamics in chemical or physical systems.
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D001696 Biomechanical Phenomena The properties, processes, and behavior of biological systems under the action of mechanical forces. Biomechanics,Kinematics,Biomechanic Phenomena,Mechanobiological Phenomena,Biomechanic,Biomechanic Phenomenas,Phenomena, Biomechanic,Phenomena, Biomechanical,Phenomena, Mechanobiological,Phenomenas, Biomechanic
D013816 Thermodynamics A rigorously mathematical analysis of energy relationships (heat, work, temperature, and equilibrium). It describes systems whose states are determined by thermal parameters, such as temperature, in addition to mechanical and electromagnetic parameters. (From Hawley's Condensed Chemical Dictionary, 12th ed) Thermodynamic
D050505 Mutant Proteins Proteins produced from GENES that have acquired MUTATIONS. Mutant Protein,Protein, Mutant,Proteins, Mutant
D054730 Protein Interaction Domains and Motifs Protein modules with conserved ligand-binding surfaces which mediate specific interaction functions in SIGNAL TRANSDUCTION PATHWAYS and the specific BINDING SITES of their cognate protein LIGANDS. Protein Interaction Domains,Protein Interaction Motifs,Binding Motifs, Protein Interaction,Protein Interaction Binding Motifs,Protein-Protein Interaction Domains,Domain, Protein Interaction,Domain, Protein-Protein Interaction,Domains, Protein Interaction,Domains, Protein-Protein Interaction,Motif, Protein Interaction,Motifs, Protein Interaction,Protein Interaction Domain,Protein Interaction Motif,Protein Protein Interaction Domains,Protein-Protein Interaction Domain

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