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  1. Insect Analogue for Intermediate Filaments Discovered
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Regardless of the group, keratins are either acidic or basic. Acidic and basic keratins bind each other to form acidic-basic heterodimers and these heterodimers then associate to make a keratin filament. There are four proteins classed as type III IF proteins, which may form homo- or heteropolymeric proteins.

In metazoan cells, there are A and B type lamins, which differ in their length and pI. Human cells have three differentially regulated genes. B-type lamins are present in every cell. A-type lamins are only expressed following gastrulation. These proteins localize to two regions of the nuclear compartment, the nuclear lamina—a proteinaceous structure layer subjacent to the inner surface of the nuclear envelope and throughout the nucleoplasm in the nucleoplasmic veil. Comparison of the lamins to vertebrate cytoskeletal IFs shows that lamins have an extra 42 residues six heptads within coil 1b.

The c-terminal tail domain contains a nuclear localization signal NLS , an Ig-fold-like domain, and in most cases a carboxy-terminal CaaX box that is isoprenylated and carboxymethylated lamin C does not have a CAAX box. Lamin A is further processed to remove the last 15 amino acids and its farnesylated cysteine. During mitosis, lamins are phosphorylated by MPF, which drives the disassembly of the lamina and the nuclear envelope. Beaded Filaments-- Filensin , Phakinin. At the plasma membrane , some keratins interact with desmosomes cell-cell adhesion and hemidesmosomes cell-matrix adhesion via adapter proteins.

Filaggrin binds to keratin fibers in epidermal cells. Plectin links vimentin to other vimentin fibers, as well as to microfilaments, microtubules, and myosin II. Kinesin is being researched and is suggested to connect vimentin to tubulin via motor proteins. Keratin filaments in epithelial cells link to desmosomes desmosomes connect the cytoskeleton together through plakoglobin , desmoplakin , desmogleins , and desmocollins ; desmin filaments are connected in a similar way in heart muscle cells. From Wikipedia, the free encyclopedia.

Further information: cytokeratin. Nature Reviews. Molecular Cell Biology. Moreover, the RH mutation can also cause dilated cardiomyopathy type A The initial crystallization studies were followed by the determination of the atomic structure of coil 1A and the second half of coil 2, then called coil 2B, for both vimentin and lamin A 43 , Whereas coil 2B was shown to form bona fide dimeric complexes, coil 1A remained monomeric in solution Even more surprising, coil 1A was also obtained as a monomer in the crystals that formed at high-protein concentration, although it assumed the left-handed helical supertwist necessary for coiled-coil formation.

Nevertheless, in the full-length protein, coil 1A is not isolated but embedded in a distinct structural context, and larger fragments containing the head domain in addition to coil 1A behave, under certain in vitro conditions, like a dimeric coiled coil In addition, the head domains of IF proteins vimentin, lamins, and keratins may help to stabilize the dimeric state. Crystallized coil 2B exhibits very much the same structural fold in lamin A and vimentin, and it is expected that keratins will exhibit a very similar structure once they are crystallized, due to their conserved amino acid sequence organization in the corresponding segment.

Therefore, coil 2 represents a truly conserved structural feature that all IF proteins exhibit in common Figure 3 B.

Insect Analogue for Intermediate Filaments Discovered

The functional meaning for this similarity is at present not clear. However, as most rules do not come without an exception, the single lamin of the nematode Caenorhabditis elegans lacks two heptads in coil 2 Nevertheless, this protein assembles into IF-like filaments and paracrystalline fibers 70 — These can be as short as 15 amino acids, as found for the tail of human keratin 19 K19 , or as long as 1, amino acids, as in the human neuronal IF protein nestin. Moreover, the nestin tail exhibits a high degree of sequence variation, even between related species such as rat and human Hence, the nestin-encoding gene is in dynamic development in vertebrate evolution.

The size of the head domain also varies widely and can be as long as amino acids, as in K5 Figure 3 B. In contrast, the nestin head domain is unusually short, with only six amino acids. The head domain is generally critical for formation of IFs, as headless IF proteins do not assemble beyond the coiled-coil stage Whether nestin and vimentin form heterodimers or whether nestin dimers associate with vimentin dimers before incorporating into IFs is not completely clear at present The three major structural IF protein groups discussed earlier see A structural blueprint for IF proteins also give rise to three more or less distinct assembly groups.

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Hence, lamins, vimentin-like IF proteins, and keratins will not coassemble into mixed IFs; rather, they completely segregate into distinct structures, even within the same cell Here, we concentrate our discussion on the in vitro assembly process of the cytoplasmic IF proteins vimentin and desmin, because it is the best understood from the biophysical characterization of the essential assembly intermediates up to the mathematical modeling of the assembly kinetics 78 — The assembly reaction can be dissected into three major steps Figure 4.

In preparation for assembly, IF proteins reconstituted from 8 M urea into low-salt buffer organize into relatively uniform tetrameric complexes of approximately half-staggered, antiparallel coiled-coil dimers; these are entirely soluble. In the first phase of assembly, which is initiated by increasing the ionic strength of the buffer, an average of eight tetramers rapidly associate laterally into unit-length filaments ULFs.

In the second phase, ULFs longitudinally anneal to form short filaments, and filament growth proceeds further by end-to-end association of filaments. All assembly steps very likely engage a number of complex molecular rearrangements, such that the flexibility of individual subdomains within the rod domain is important for successive interactions Schematic representation of the three major phases of cytoplasmic IF assembly.

In phase 1, eight tetrameric subunits made from two antiparallel, half-staggered coiled-coil dimers associate laterally to form ULFs after initiation of assembly.

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Every single vimentin molecule is represented by one cylinder; coil 1 of each molecule is colored dark red, and coil 2 is colored yellow. In phase 3, after about ten minutes of assembly, filaments have radially compacted to a diameter of approximately 11 nm. Adapted with permission from Journal of biological chemistry A major determinant of the annealing reaction, in which the ends of two filaments mediate the longitudinal fusion of two ULFs or short filaments, may reside in the structural state of the two end segments of the rod.

Taking the comparatively weak interaction between two coil 1A chains as an argument, it was previously suggested that the two-stranded coiled coil of the vimentin dimer may partially open in its coil 1A region to facilitate longitudinal annealing, followed by a lock-in-type reaction, thereby generating stable joints between annealed segments 43 , These interactions may be directly affected by phosphorylation of various serine residues in the head domain of vimentin, which can lead to the fragmentation and dissociation of vimentin IFs 85 — Consistent with the idea that the conserved end segments of the rod are important for elongation, chemical cross-linking experiments have revealed an overlap-type interaction of the amino- and carboxyterminal domains of the vimentin rod 1.

These types of interactions may represent major molecular contacts mediating the longitudinal annealing of ULFs and short filaments. As expected given that there are three distinct assembly groups discussed earlier in The IF assembly mechanism: three distinct assembly groups , the overall structure of different IFs varies considerably.

Actually, the diameter of IFs, as measured in ultrathin sections from various tissues, was early on referred to as 7—11 nm, indicating high structural variability between the various IFs assembled from distinct IF proteins Note that the cross-sectional area of an nm-diameter filament is twice that of a 7-nm-diameter IF, and therefore it harbors twice as many subunits as the thinner filament.

Most likely, the resistance of an IF to mechanical stress increases with the number of subunits within a filament, and therefore this structural polymorphism may be of functional importance. Nevertheless, some general features are found in every IF, be it a lamin filament in the nucleus, a desmin filament in a muscle cell, or a keratin filament in an epithelial cell First, all IFs are apolar due to the fact that the principal structural building block within an IF is a tetramer assembled from two antiparallel oriented, dimeric coiled coils.

Second, all IFs are highly resistant to extraction with high-ionic-strength buffers, no matter what tissue they are isolated from.

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This behavior indicates that IFs are held together via an extensive network of both charged and hydrophobic interactions. Third, disease-associated IF protein mutations that affect IF assembly in vitro also disturb IF formation in transfected cells and transgenic animals 52 , 90 , A powerful proof of principle as to how predictions derived from both IF protein structure obtained by X-ray crystallography and the behavior of the recombinant protein in vitro translate into IF assembly in living cells has been provided by analysis of vimentin mutated at a specific site in coil 1A.

Compared with the wild-type coil 1A peptide, the mutant peptide exhibited a much higher melting temperature, indicating the formation of strong inter-helical forces Moreover, when the corresponding amino acid change was introduced into full-length vimentin, its in vitro assembly was completely arrested at the ULF stage Upon transfection of this vimentin mutant into vimentin-deficient mouse embryonic fibroblasts, the cells displayed a very distinct, dot-like fluorescent signal pattern indicative of the formation of rather uniform structures Figure 5 C.

Impact of a point mutation in vimentin coil 1A on filament elongation both in vitro and in vivo. A Hypothetical model depicting that coil 1A may have a tendency to open up with the authentic tyrosine , shown in extreme conformation. B Side stereo view of the atomic structure of coil 1A from the vimentin mutant YL, exhibiting a bona fide coiled coil.

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Residues bounded by the first and the last knobs-into-hole interaction are colored in cyan. Residues at a positions are shown in yellow and those at d positions are shown in magenta. The N terminus is marked N, and the C terminus is marked C. The residue types and numbers of the core positions are indicated. C Transfection of mouse embryonic fibroblasts derived from vimentin-knockout mice with the vimentin mutant YL, followed by indirect immunofluorescence microscopy with antibodies specific for human vimentin, revealing dot-like structures exclusively. Note the regular shaped particles that on occasion are lined up, possibly being situated on a fibrillar structure such as a MT inset.

A is reproduced with permission from EMBO journal B and C are reproduced with permission from Journal of molecular biology At present, 86 distinct human pathologies are known to arise from mutations in IF protein—encoding genes refs. The most mutated gene is that encoding human lamin A and lamin C.

At present, mutations in this gene have been linked to at least ten different disease entities 96 — Although, the respective pathomechanisms have remained elusive, several plausible suggestions bearing on their central role as integrators of cellular architecture have been made.

These range from interference with resistance of nuclei and whole cells to mechanical stress, to structural alterations in chromatin organization, to modulation of stem cell activities, to changes in gene expression programs and an increase in genomic instability 99 — Mutations in the genes encoding the epidermal K5 and K14 were the first to be identified to cause disease reviewed in refs.

In the basal cell layer of the epidermis, the mutated keratin filaments aggregate heavily and lose their normal connection to desmosomes and hemidesmosomes. Hence, these mutations in K5 and K14 interfere with the proper generation of a functional cytoskeleton and, as a consequence, with the stress-absorbing functions of IFs. Both the loss of normal connection to desmosomes and hemidesmosomes and the defect in stress-absorption are evidently central to the tissue fragility observed in individuals carrying these mutations in K5 and K14, although other processes, such as signaling and protein turnover, may well be affected and contribute to the pathophysiology As a consequence, the skin of people born with defective K14 is highly fragile One of the most recent examples of mutations in IF protein—encoding genes that contribute to tissue malfunction relates to the eye lens: a mutation in coil 1B of vimentin, GluLys, has recently been demonstrated to underlie the formation of cataract This glutamic acid is absolutely conserved in vimentins from sharks to humans, and its change to lysine results in a strong kinetic in vitro assembly defect without, however, having a gross effect on the morphology of the mature IF Desmin mutations affect IF assembly.


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The muscle-specific IF protein desmin is, in evolutionary terms, rather old, as highly conserved homologs are found in muscle cells from the invertebrate Styela to mammals including humans 49 , Moreover, all these desmins, including the Styela protein, follow the ULF-type assembly pathway, as demonstrated by in vitro studies with recombinant proteins This conserved assembly behavior indicates that structural and functional aspects coevolved early on, even before vertebrate development started.

The first disease-associated mutation in the human desmin-encoding gene was identified about ten years ago Analysis of the effects of the mutation, which led to a deletion of seven amino acids in coil 1B, demonstrated that it compromised desmin IF assembly both in vitro and in transfected cells. This observation provided a molecular explanation for the huge sarcoplasmic desmin aggregates found in patient muscle and the concomitant severe disturbance in the ordered parallel alignment of sarcomeres within individual myofibers.