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  • BIOLOGY  (21)
  • 1
    Keywords: BIOLOGY ; ARCHITECTURE ; cytoskeleton ; PROTEIN ; CELL ; MICROSCOPY ; intermediate filament ; AMINO-ACID-SEQUENCE ; CROSS-LINKING ; review ; DESMIN ; ROD DOMAIN ; HUMAN VIMENTIN ; KERATIN FILAMENTS ; RAY SOLUTION SCATTERING ; SWITZERLAND ; COILED-COIL
    Type of Publication: Book chapter
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  • 2
    Keywords: CELL ; Germany ; human ; DISEASE ; DISEASES ; DISTINCT ; GENE ; PROTEIN ; PROTEINS ; INTERMEDIATE-SIZED FILAMENTS ; IMPACT ; BIOLOGY ; NUMBER ; MUTATION ; MUTATIONS ; US ; cytoskeleton ; intermediate filaments ; vimentin ; DE-NOVO ; ALPHA-B-CRYSTALLIN ; MICE LACKING DESMIN ; HUMAN-DISEASE ; ARCHITECTURE ; intermediate filament ; CHICKEN SKELETAL-MUSCLE ; desmin-related myopathy ; desminopathy ; filament assembly ; HEAD DOMAIN ; IMMUNOCYTOCHEMICAL ANALYSIS ; MYOFIBRILLAR MYOPATHY ; RESTRICTIVE CARDIOMYOPATHY ; VERTEBRATE SMOOTH-MUSCLE
    Abstract: Desmin, the major intermediate filament (IF) protein of muscle, is evolutionarily highly conserved from shark to man. Recently, an increasing number of mutations of the desmin gene has been described to be associated with human diseases such as certain skeletal and cardiac myopathies. These diseases are histologically characterised by intracellular aggregates containing desmin and various associated proteins. Although there is progress regarding our knowledge on the cellular function of desmin within the cytoskeleton, the impact of each distinct mutation is currently not understood at all. In order to get insight into how such mutations affect filament assembly and their integration into the cytoskeleton we need to establish IF structure at atomic detail. Recent progress in determining the dimer structure of the desmin-related IF-protein vimentin allows us to assess how such mutations may affect desmin filament architecture. (C) 2004 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15477095
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  • 3
    Keywords: CELLS ; IN-VITRO ; CELL ; COMBINATION ; PROTEIN ; PROTEINS ; DIFFERENTIATION ; TISSUE ; COMPLEX ; COMPLEXES ; FAMILY ; primary ; DOMAIN ; TISSUES ; BIOLOGY ; MEMBER ; MEMBERS ; polymorphism ; ELEMENT ; PATTERNS ; ELEMENTS ; NUCLEUS ; CRYSTAL-STRUCTURE ; MUSCLE ; STABILITY ; tomography ; intermediate filaments ; INTERMEDIATE-FILAMENTS ; Jun ; keratin ; vimentin ; epidermis ; DIMER ; ATOMIC-STRUCTURE ; intermediate filament ; molecular ; ONCOLOGY ; PROGRAM ; review ; RE ; FAMILIES ; PATTERN ; ELECTRON-MICROSCOPY ; assembly ; COILED-COIL ; EPIDERMAL KERATIN FILAMENTS ; ROD DOMAIN ; analysis ; methods ; LONG ; USA ; FILAMENTS ; STEM ; modeling ; X-RAY ; SHAPE ; cryo-electron tomography ; FIBROUS PROTEINS ; HELICAL COILED COILS ; IV ALPHA-INTERNEXIN ; PLASTICITY ; small-angle X-ray scattering ; TRICHOCYTE KERATIN
    Abstract: Intermediate filaments (IFs) represent one of the prominent cytoskeletal elements of metazoan cells. Their constituent proteins are coded by a multigene family, whose members are expressed in complex patterns that are controlled by developmental programs of differentiation. Hence, IF proteins found in epidermis differ significantly from those in muscle or neuronal tissues. Due to their fibrous nature, which stems from a fairly conserved central alpha-helical coiled-coil rod domain, IF proteins have long resisted crystallization and thus determination of their atomic structure. Since they represent the primary structural elements that determine the shape of the nucleus and the cell more generally, a major challenge is to arrive at a more rational understanding of how their nanomechanical properties effect the stability and plasticity of cells and tissues. Here, we review recent structural results of the coiled-coil dimer, assembly intermediates and growing filaments that have been obtained by a hybrid methods approach involving a rigorous combination of X-ray crystallography, small angle X-ray scattering, cryo-electron tomography, computational analysis and molecular modeling. (c) 2007 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17521629
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  • 4
    Keywords: IN-VITRO ; Germany ; MICROSCOPY ; DISEASE ; PROTEIN ; PROTEINS ; DYNAMICS ; BIOLOGY ; fibroblasts ; DAMAGE ; LENGTH ; vimentin ; ATOMIC-FORCE MICROSCOPY ; SMOOTH-MUSCLE ; electron microscopy ; molecular biology ; DEPENDENCE ; DESMIN ; desmin and vimentin intermediate filament ; ELASTIC LIGHT-SCATTERING ; F-ACTIN SOLUTIONS ; MICRORHEOLOGY ; persistence length ; rheology ; strain stiffening ; THERMAL FLUCTUATIONS
    Abstract: We have investigated the viscoelastic properties of the cytoplasmic intermediate filament (IF) proteins desmin and vimentin. Mechanical measurements were supported by time-dependent electron microscopy studies of the assembly process under similar conditions. Network formation starts within 2 min, but it takes more than 30 min until equilibrium mechanical network strength is reached. Filament bundling is more pronounced for desmin than for vimentin. Desmin filaments (persistence length l(p) approximate to 900 nm) are stiffer than vimentin filaments (l(p) approximate to 400 nm), but both IFs are much more flexible than microfilaments. e concentration dependence of the plateau modulus G(0) similar to c(alpha) is much weaker than predicted theoretically for networks of semiflexible filaments. This is more pronounced for vimentin (alpha = 0.47) than for desmin (alpha = 0.70). Both networks exhibit strain stiffening at large shear deformations. At the transition from linear to nonlinear viscoelastic response, only desmin shows characteristics of nonaffine network deformation. Strain stiffening and the maximum modulus occur at strain amplitudes about an order of magnitude larger than those for microfilaments. This is probably attributable to axial slippage within the tetramer building blocks of the IFs. Network deformation beyond a critical strain gamma(max) results in irreversible damage. Strain stiffening sets in at lower concentrations, is more pronounced, and is less sensitive to ionic strength for desmin than for vimentin. Hence, desmin exhibits strain stiffening even at low-salt concentrations, which is not observed for vimentin, and we conclude that the strength of electrostatic repulsion compared to the strength of attractive interactions forming the network junctions is significantly weaker for desmin than for vimentin filaments. These findings indicate that both IFs exhibit distinct mechanical properties that are adapted to their respective cellular surroundings [i.e., myocytes (desmin) and fibroblasts (vimentin)]. (C) 2009 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19281820
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  • 5
    Keywords: CELLS ; IN-VITRO ; CELL ; VITRO ; NETWORK ; NETWORKS ; PROTEIN ; PROTEINS ; MECHANISM ; DOMAIN ; BIOLOGY ; VARIANTS ; ACID ; STRESS ; LENGTH ; cytoskeleton ; vimentin ; AMINO-ACIDS ; ATOMIC-FORCE MICROSCOPY ; BEHAVIOR ; DOMAINS ; ORIGIN ; VARIANT ; SCIENCE ; F-ACTIN ; PERSISTENCE ; ELASTICITY ; amino acids ; VISCOELASTIC PROPERTIES ; rheology ; BIOPOLYMER NETWORKS ; ACTIN SOLUTIONS ; cell mechanics ; DEFICIENT CELLS ; FLUORESCENT INDICATOR MAG-INDO-1
    Abstract: Intermediate filament networks in the cytoplasm and nucleus are critical for the mechanical integrity of metazoan cells. However, the mechanism of crosslinking in these networks and the origins of their mechanical properties are not understood. Here, we study the elastic behavior of in vitro networks of the intermediate filament protein vimentin. Rheological experiments reveal that vimentin networks stiffen with increasing concentrations of Ca2+ and Mg2+, showing that divalent cations act as crosslinkers. We quantitatively describe the elastic response of vimentin networks over five decades of applied stress using a theory that treats the divalent cations as crosslinkers: at low stress, the behavior is entropic in origin, and increasing stress pulls out thermal fluctuations from single filaments, giving rise to a nonlinear response; at high stress, enthalpic stretching of individual filaments significantly modifies the nonlinearity. We investigate the elastic properties of networks formed by a series of protein variants with stepwise tail truncations and find that the last 11 amino acids of the C-terminal tail domain mediate crosslinking by divalent ions. We determined the single-filament persistence length, l(P) approximate to 0.5 mu m, and Young's modulus, Y approximate to 9 MPa; both are consistent with literature values. Our results provide insight into a crosslinking mechanism for vimentin networks and suggest that divalent ions may help regulate the cytoskeletal structure and mechanical properties of cells. (C) 2010 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 20447406
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  • 6
    Keywords: CELLS ; CELL ; Germany ; MICROSCOPY ; SYSTEM ; SITE ; SITES ; PROTEINS ; COMPLEX ; COMPLEXES ; CONTRAST ; DYNAMICS ; BIOLOGY ; polymorphism ; DIVERSITY ; MICROTUBULES ; tomography ; intermediate filaments ; INTERMEDIATE-FILAMENTS ; vimentin ; ORGANIZATION ; DIMER ; RECONSTRUCTION ; CRYOELECTRON MICROSCOPY ; ATOMIC-STRUCTURE ; intermediate filament ; MOLECULAR-BASIS ; ELECTRON-MICROSCOPY ; COILED-COIL ; MOLECULAR ARCHITECTURE ; KERATIN FILAMENTS ; microtubule ; USA ; DIMERS ; UNIT ; SPECIMENS ; FILAMENTS ; 3D structure ; cryo-electron tomography ; protofibrils
    Abstract: Vimentin polymerizes via complex lateral interactions of coiled-coil dimers into long, flexible filaments referred to as intermediate filaments (IFs). Intermediate in diameter between microtubules and microfilaments, IFs constitute the third cytoskeletal filament system of metazoan cells. Here we investigated the molecular basis of the 3-D architecture of vimentin IFs by cryo-electron microscopy (cryo-EM) as well as cryo-electron tomography (Cryo-ET) 3-D reconstruction. We demonstrate that vimentin filaments in cross-section exhibit predominantly a four-stranded protofibrilar organization with a right-handed supertwist with a helical pitch of about 96 nm. Compact filaments imaged by cryo-EM appear surprisingly straight and hence appear very stiff. In addition, IFs exhibited an increased flexibility at sites of partial unraveling. This is in strong contrast to chemically fixed, negatively stained preparations of vimentin filaments that generally exhibit smooth bending without untwisting. At some point along the filament unraveling may be triggered and propagates in a cooperative manner so that long stretches of filaments appear to have unraveled rapidly in a coordinated fashion. (c) 2006 Elsevier Inc. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17289402
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  • 7
    Keywords: CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; CELL ; Germany ; human ; SYSTEM ; DISEASE ; PROTEIN ; PROTEINS ; TISSUE ; LINES ; MICE ; TIME ; DOMAIN ; TISSUES ; BIOLOGY ; DELETION ; MOUSE ; MUTANT ; NO ; TRANSGENIC MICE ; HUMANS ; MUTATION ; LINE ; MUTATIONS ; cytoskeleton ; intermediate filaments ; keratin ; PHENOTYPE ; vimentin ; pathology ; PROTEASOME ; ALPHA-B-CRYSTALLIN ; EPIDERMOLYSIS-BULLOSA SIMPLEX ; INTERMEDIATE-FILAMENT PROTEINS ; keratins ; INCREASE ; POINT MUTATIONS ; ENGLAND ; NOV ; HSP70 ; FOCAL ADHESIONS ; response ; proteasomes ; NO EVIDENCE ; CELL BIOLOGY ; Cataract formation ; CHAPERONE ACTIVITY ; Chaperones ; Dominant-negative mutation ; EYE LENS ; FIBER CELL-DIFFERENTIATION ; Mouse model systems ; Protein misfolding
    Abstract: Vimentin is the main intermediate filament ( IF) protein of mesenchymal cells and tissues. Unlike other IF-/- mice, vimentin(-/-) mice provided no evidence of an involvement of vimentin in the development of a specific disease. Therefore, we generated two transgenic mouse lines, one with a ( R113C) point mutation in the IF-consensus motif in coil1A and one with the complete deletion of coil 2B of the rod domain. In epidermal keratins and desmin, point mutations in these parts of the alpha-helical rod domain cause keratinopathies and desminopathies, respectively. Here, we demonstrate that substoichiometric amounts of vimentin carrying the R113C point mutation disrupted the endogenous vimentin network in all tissues examined but caused a disease phenotype only in the eye lens, leading to a posterior cataract that was paralleled by the formation of extensive protein aggregates in lens fibre cells. Unexpectedly, central, postmitotic fibres became depleted of aggregates, indicating that they were actively removed. In line with an increase in misfolded proteins, the amounts of Hsp70 and ubiquitylated vimentin were increased, and proteasome activity was raised. We demonstrate here for the first time that the expression of mutated vimentin induces a protein-stress response that contributes to disease pathology in mice, and hypothesise that vimentin mutations cause cataracts in humans
    Type of Publication: Journal article published
    PubMed ID: 18940912
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  • 8
    Keywords: ENDOTHELIAL-CELLS ; EXPRESSION ; CELL ; DISEASE ; GENE ; GENE-EXPRESSION ; DIFFERENTIATION ; MECHANISM ; BIOLOGY ; MOLECULAR-BIOLOGY ; DISORDER ; CHROMATIN ; gene expression ; CAENORHABDITIS-ELEGANS ; MAMMALIAN-CELLS ; INTERMEDIATE-FILAMENTS ; INSIGHTS ; SPATIAL-ORGANIZATION ; ORGANIZATION ; MUSCULAR-DYSTROPHY ; molecular biology ; molecular ; MECHANICAL-PROPERTIES ; NUCLEAR ; USA ; LAMIN-A ; modification ; epigenetic ; DEVELOPMENTAL CONTROL ; ACTIN-BINDING PROTEINS ; GILFORD-PROGERIA-SYNDROME
    Abstract: Changes in the shape and structural organization of the cell nucleus occur during many fundamental processes including development, differentiation and aging. In many of these processes, the cell responds to physical forces by altering gene expression within the nucleus. How the nucleus itself senses and responds to such mechanical cues is not well understood. In addition to these external forces, epigenetic modifications of chromatin structure inside the nucleus could also alter its physical properties. To achieve a better understanding, we need to elucidate the relationship between nuclear structure and material properties. Recently, new approaches have been developed to systematically investigate nuclear mechanical properties. These experiments provide important new insights into the disease mechanism of a growing class of tissue-specific disorders termed 'nuclear envelopathies'. Here we review our current understanding of what determines the shape and mechanical properties of the cell nucleus
    Type of Publication: Journal article published
    PubMed ID: 18293361
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  • 9
    Keywords: PEPTIDE ; CELLS ; IN-VITRO ; CELL ; human ; VITRO ; PROTEIN ; DOMAIN ; BIOLOGY ; SPECTROSCOPY ; FORM ; SUBUNIT ; MUTATION ; CRYSTAL-STRUCTURE ; STABILITY ; INTERMEDIATE-FILAMENTS ; vimentin ; DIMER ; lamin ; DOMAINS ; ATOMIC-STRUCTURE ; intermediate filament ; SINGLE ; molecular biology ; assembly ; REARRANGEMENT ; coiled coil ; COILED-COIL ; nuclear lamins ; TEMPERATURE ; AMINO-ACID SUBSTITUTIONS ; circular dichroism ; POSITION ; STATE ; biophysical analysis ; CONSENSUS MOTIF ; GCN4 LEUCINE-ZIPPER ; HYDROPHOBIC CORE ; Oligomerisation ; OLIGOMERIZATION STATE ; PROTEIN STRUCTURES
    Abstract: Interestingly, our previously published structure of the coil 1A fragment of the human intermediate filament protein vimentin turned out to be a monomeric alpha-helical coil instead of the expected dimeric coiled coil. However, the 39-amino-acid-long helix had an intrinsic curvature compatible with a coiled coil. We have now designed four mutants of vimentin coil 1A, modifying key a and d positions in the heptad repeat pattern, with the aim of investigating the molecular criteria that are needed to stabilize a dimeric coiled-coil structure. We have analysed the biophysical properties of the mutants by circular dichroism spectroscopy, analytical ultracentrifugation and X-ray crystallography. All four mutants exhibited an increased stability over the wild type as indicated by a rise in the melting temperature (T-m). At a concentration of 0.1 mg/ml, the T-m of the peptide with the single point mutation Y117L increased dramatically by 46 degrees C compared with the wild-type peptide. In general, the introduction of a single stabilizing point mutation at an a or a d position did induce the formation of a stable dimer as demonstrated by sedimentation equilibrium experiments. The dimeric oligomerisation state of the Y117L peptide was furthermore confirmed by Xray crystallography, which yielded a structure with a genuine coiled-coil geometry. Most notably, when this mutation was introduced into full-length vimentin, filament assembly was completely arrested at the unit-length filament (ULF) level, both in vitro and in cDNA-transfected cultured cells. Therefore, the low propensity of the wild-type coil 1A to form a stable two-stranded coiled coil is most likely a prerequisite for the end-to-end annealing of ULFs into filaments. Accordingly, the coil 1A domains might "switch" from a dimeric alpha-helical coiled coil into a more open structure, thus mediating, within the ULFs, the conformational rearrangements of the tetrameric subunits that are needed for the intermediate filament elongation reaction. (C) 2009 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19422834
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  • 10
    Keywords: CELLS ; BLOOD ; CELL ; COMBINATION ; Germany ; human ; SITES ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; DIFFERENTIATION ; COMPLEX ; COMPLEXES ; INFECTION ; BIOLOGY ; FORM ; NUCLEUS ; cytoskeleton ; vimentin ; lamin ; MEMBRANE PROTEIN ; MONOCYTE ; ACTIN CYTOSKELETON ; RETINOIC ACID ; BINDING PROTEIN ; BLOOD-VESSELS ; USA ; macrophage ; adaptation ; MONOCYTES ; STATE ; neutrophil ; HL-60 CELLS ; WELL ; ENVELOPE ARCHITECTURE ; LAMIN-B-RECEPTOR ; Nuclear enveloped ; PROMYELOCYTIC LEUKEMIA-CELLS
    Abstract: The major blood granulocyte (neutrophil) is rapidly recruited to sites of bacterial and fungal infections. It is a highly malleable cell, allowing it to squeeze out of blood vessels and migrate through tight tissue spaces. The human granulocyte nucleus is lobulated and exhibits a paucity of nuclear lamins, increasing its capability for deformation. The present study examined the existence of protein connections between the nuclear envelope and cytoskeletal elements (the LINC complex) in differentiated cell states (i.e. granulocytic, monocytic and macrophage) of the human leukemic cell line HL-60, as well as in human blood leukocytes. HL-60 granulocytes exhibited a deficiency of several LINC complex proteins (i.e. nesprin I giant, nesprin 2 giant, SUN1, plectin and vimentin); whereas, the macrophage state revealed nesprin I giant, plectin and vimentin. Both states possessed SUN2 in the nuclear envelope. Parallel differences were observed with some of the LINC complex proteins in isolated human blood leukocytes, including macrophage cells derived from blood monocytes. The present study documenting the paucity of LINC complex proteins in granulocytic forms, in combination with previous data on granulocyte nuclear shape and nuclear envelope composition, suggest the hypothesis that these adaptations evolved to facilitate granulocyte cellular malleability. (C) 2008 Elsevier GmbH. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19019491
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