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• W1979156924 abstract "A new model for stratum corneum keratin structure, function, and formation is presented. The structural and functional part of the model, which hereafter is referred to as “the cubic rod-packing model”, postulates that stratum corneum keratin intermediate filaments are arranged according to a cubic-like rod-packing symmetry with or without the presence of an intracellular lipid membrane with cubic-like symmetry enveloping each individual filament. The new model could account for (i) the cryo-electron density pattern of the native corneocyte keratin matrix, (ii) the X-ray diffraction patterns, (iii) the swelling behavior, and (iv) the mechanical properties of mammalian stratum corneum. The morphogenetic part of the model, which hereafter is referred to as “the membrane templating model”, postulates the presence in cellular space of a highly dynamic small lattice parameter (<30 nm) membrane structure with cubic-like symmetry, to which keratin is associated. It further proposes that membrane templating, rather than spontaneous self-assembly, is responsible for keratin intermediate filament formation and dynamics. The new model could account for (i) the cryo-electron density patterns of the native keratinocyte cytoplasmic space, (ii) the characteristic features of the keratin network formation process, (iii) the dynamic properties of keratin intermediate filaments, (iv) the close lipid association of keratin, (v) the insolubility in non-denaturating buffers and pronounced polymorphism of keratin assembled in vitro, and (vi) the measured reduction in cell volume and hydration level between the stratum granulosum and stratum corneum. Further, using cryo-transmission electron microscopy on native, fully hydrated, vitreous epidermis we show that the subfilametous keratin electron density pattern consists, both in corneocytes and in viable keratinocytes, of one axial subfilament surrounded by an undetermined number of peripheral subfilaments forming filaments with a diameter of ∼8 nm. A new model for stratum corneum keratin structure, function, and formation is presented. The structural and functional part of the model, which hereafter is referred to as “the cubic rod-packing model”, postulates that stratum corneum keratin intermediate filaments are arranged according to a cubic-like rod-packing symmetry with or without the presence of an intracellular lipid membrane with cubic-like symmetry enveloping each individual filament. The new model could account for (i) the cryo-electron density pattern of the native corneocyte keratin matrix, (ii) the X-ray diffraction patterns, (iii) the swelling behavior, and (iv) the mechanical properties of mammalian stratum corneum. The morphogenetic part of the model, which hereafter is referred to as “the membrane templating model”, postulates the presence in cellular space of a highly dynamic small lattice parameter (<30 nm) membrane structure with cubic-like symmetry, to which keratin is associated. It further proposes that membrane templating, rather than spontaneous self-assembly, is responsible for keratin intermediate filament formation and dynamics. The new model could account for (i) the cryo-electron density patterns of the native keratinocyte cytoplasmic space, (ii) the characteristic features of the keratin network formation process, (iii) the dynamic properties of keratin intermediate filaments, (iv) the close lipid association of keratin, (v) the insolubility in non-denaturating buffers and pronounced polymorphism of keratin assembled in vitro, and (vi) the measured reduction in cell volume and hydration level between the stratum granulosum and stratum corneum. Further, using cryo-transmission electron microscopy on native, fully hydrated, vitreous epidermis we show that the subfilametous keratin electron density pattern consists, both in corneocytes and in viable keratinocytes, of one axial subfilament surrounded by an undetermined number of peripheral subfilaments forming filaments with a diameter of ∼8 nm. The objective of this study is to present a new model for the structure, function, and formation of the corneocyte matrix of the mammalian stratum corneum. The structural organization of the keratin intermediate filament-dominated stratum corneum corneocyte matrix is of major importance for the barrier properties of skin, the water-holding capacity of skin, the appearance (i.e., optical properties) of skin, the mechanical strength and elastic resilience of skin, and skin pathologies characterized by alterations of one or some of these properties (e.g., dry skin, atopic dermatitis, psoriasis, ichthyosis). But there still lacks a comprehensive model capable of explaining keratin intermediate filament structure, function, and formation when newer findings regarding the native structural organization of fully hydrated epidermis (cf.53Norlén L.P.O. Al-Amoudi A. Dubochet J. A cryo-transmission electron microscopy study of skin barrier formation.J Invest Dermatol. 2003; 120: 555-560Crossref PubMed Scopus (57) Google Scholar) 1Al-Amoudi A, Dubochet J, Norlén L: A high-resolution cryo-transmission electron microscopy study of native skin barrier structure and formation. J Cell Biol, 2004 (submitted)1Al-Amoudi A, Dubochet J, Norlén L: A high-resolution cryo-transmission electron microscopy study of native skin barrier structure and formation. J Cell Biol, 2004 (submitted) have been taken into account. Such a theoretical model may provide for a rational design of experimental studies on skin diseases, skin permeability, topical drug administration, skin protection, cosmetic formulations, etc. Intermediate filaments are ubiquitous structures in the vast majority of animal cells. Among these filaments, keratins account for about three-quarters of all known proteins. The molecular architecture of intermediate filaments remains, however, speculative. To date, no major portion of an intermediate filament chain has been crystallized and there has been no atomic-level nuclear magnetic resonance data deduced either (59Parry D.A.D. Steinert P.M. Intermediate filaments: Molecular architecture, assembly, dynamics and polymorphism.Quart Rev Biophys. 1999; 32: 99-187Crossref PubMed Scopus (192) Google Scholar, p 123, 168). Also, the higher-order structural organization(s) of intermediate filaments remain(s) undetermined (78Van Amerongen H. Kooijman M. Bloemendal M. Transient electric birefringence in the study of intermediate filament assembly.in: Herrmann H. Harris J.R. Intermediate Filaments—Subcellular Biochemistry. Plenum Press, New York1998: 399-421Google Scholar, p 414). Conventional transmission electron microscopy of stained sections of wool has shown keratin intermediate filaments ∼7–8 nm in diameter with an electron lucent central core surrounded by an electron lucent annular ring. In the paracortex of wool and quill, the keratin filaments seem quasi-hexagonally packed and embedded in a matrix that preferentially takes up stain (22Fraser R.D.B. MacRae T.P. Rogers G.E. Keratins: Their Composition, Structure and Biosynthesis. Charles C. Thomas Publisher, Springfield, IL, USA1972Google Scholar, p 61). Keratin intermediate filaments from various cell types reassembled in vitro, however, have been measured to ∼10 nm in diameter, and in many instances even somewhat larger. It has therefore been proposed that the trichocyte keratin intermediate filament molecules differ in their packing from those of other cell types (59Parry D.A.D. Steinert P.M. Intermediate filaments: Molecular architecture, assembly, dynamics and polymorphism.Quart Rev Biophys. 1999; 32: 99-187Crossref PubMed Scopus (192) Google Scholar, p 133). In the 1950s,61Pauling L. Corey R.B. Compound helical configurations of polypeptide chains: Structure of proteins of the α-keratin type.Nature. 1953; 171: 59-61Crossref PubMed Scopus (208) Google Scholar suggested that keratin intermediate filaments were composed of seven single polypeptide chains, each with the configuration of a compound α-helix, where six such chains twisted about a seventh to form a seven-strand cable with a diameter of ∼3 nm. Later,59Parry D.A.D. Steinert P.M. Intermediate filaments: Molecular architecture, assembly, dynamics and polymorphism.Quart Rev Biophys. 1999; 32: 99-187Crossref PubMed Scopus (192) Google Scholar proposed that keratin intermediate filaments were composed of four 8-chain “protofibril” entities each with a diameter of 4.5 nm. The eight-chain protofibrils were proposed to consist of four pairs of two-stranded coiled-coil molecules forming a “four-chain complex”. Also,27Herrmann H. Aebi U. Intermediate filament assembly: Fibrillogenesis is driven by decisive dimer-dimer interactions.Curr Opin Struct Biol. 1998; 8: 177-185https://doi.org/10.1016/S0959-440X(98)80035-3Crossref PubMed Scopus (137) Google Scholar have suggested that eight 4-chain “protofilaments”, each with a diameter of 2.8 nm, pack together to form a 10-nm intermediate filament. The three-dimensional higher-order organization of keratin intermediate filaments in the stratum corneum has been the subject of much debate over the last 50 y. Initially, it was suggested that groups of seven 10 nm keratin intermediate filaments aggregated into 25 nm fibrils with an 8 nm lipid layer covering the surface of each fibril, thus forming lipoprotein fibrils with a total diameter of ∼40 nm. The fibrils were proposed to be oriented in a plane parallel to the plane of the flattened stratum corneum cells (72Swanbeck G. On the keratin fibrils of the skin. An X-ray small angle scattering study of the horny layer.J Ultrastruct Res. 1959; 3: 51-57Crossref PubMed Scopus (11) Google Scholar;3Baden H.P. Goldsmith L.A. The structural protein of epidermis.J Invest Dermatol. 1972; 59: 66-76Crossref PubMed Scopus (15) Google Scholar;73Swanbeck G. Macromolecular organisation of epidermal keratin.Acta Derm Venereol (Stockh). 1959; 39: 1-37PubMed Google Scholar). The presence of intracellular lipids in the corneocyte matrix was later contested (7Breathnach A.S. Goodman T. Stolinski C. Gross M. Freeze fracture replication of cells of stratum corneum of human epidermis.J Anat. 1973; 114: 65-81PubMed Google Scholar;17Elias P.M. Friend D.S. The permeability barrier in mammalian epidermis.J Cell Biol. 1975; 65: 180-191https://doi.org/10.1083/jcb.65.1.180Crossref PubMed Scopus (541) Google Scholar), and then reaffirmed (24Garson J.-C. Doucet J. Lévêque J.-L. Tsoucaris G. Oriented structure in human stratum corneum revealed by x-ray diffraction.J Invest Dermatol. 1991; 96: 43-49https://doi.org/10.1111/1523-1747.ep12514716Crossref PubMed Scopus (124) Google Scholar). Today, the leading opinion seems to favor the absence of substantial amounts of intracellular membrane lipids. Further, the cell matrix is most often regarded as a network of randomly oriented (in two or three dimensions) keratin intermediate filaments embedded in a filaggrin/free amino acid-rich protein/water ground substance (9Brody I. The keratinization of epidermal cells of normal guinea pig skin as revealed by electron microscopy.J Ultrastruct Res. 1959; 2: 482-511Crossref Scopus (173) Google Scholar;41Matoltsy A.G. Keratinization.J Invest Dermatol. 1976; 67: 20-25https://doi.org/10.1111/1523-1747.ep12512473Crossref PubMed Scopus (123) Google Scholar;55Odland F. Structure of the skin.in: Goldsmith L.A. Physiology, Biochemistry and Molecular Biology of the Skin. Oxford University Press, New York1991: 3-62Google Scholar, p 11). Classical transmission electron microscopy studies have revealed a keratin “pattern”, or keratin “network”, filling the cytoplasmic space of stratum corneum cells (9Brody I. The keratinization of epidermal cells of normal guinea pig skin as revealed by electron microscopy.J Ultrastruct Res. 1959; 2: 482-511Crossref Scopus (173) Google Scholar,10Brody I. The ultrastructure of the tonofibrils in the keratinization process of normal human epidermis.J Ultrastruct Res. 1960; 4: 264-297Crossref Scopus (119) Google Scholar). At high magnification, the individual keratin filaments appear electron lucent with a diameter of ∼7-10 nm, enclosed in a dark, amorphous continuum. The proposed overall filament distribution in the plane of the corneocytes (cf.73Swanbeck G. Macromolecular organisation of epidermal keratin.Acta Derm Venereol (Stockh). 1959; 39: 1-37PubMed Google Scholar) is not supported by these studies. In this study, cryo-transmission electron microscopy of native (i.e., freshly taken, non-pretreated), fully hydrated, vitreous epidermal sections (cf.53Norlén L.P.O. Al-Amoudi A. Dubochet J. A cryo-transmission electron microscopy study of skin barrier formation.J Invest Dermatol. 2003; 120: 555-560Crossref PubMed Scopus (57) Google Scholar) 1Al-Amoudi A, Dubochet J, Norlén L: A high-resolution cryo-transmission electron microscopy study of native skin barrier structure and formation. J Cell Biol, 2004 (submitted) was used in order to obtain a more realistic, as well as a more detailed, view of the endogenous structural organization of human forearm epidermis than is possible with conventional electron microscopy of chemically fixed, dehydrated, resin-embedded samples. For comparative reasons, conventional sample preparations were performed in parallel with direct vitreous cryo-fixation. In human forearm epidermis prepared by direct vitreous cryo-fixation without pre-treatment, the corneocyte density, size, and form were approximately homogenous all through the stratum corneum (Fig S1), with the exception of the lowermost corneocytes facing the underlying stratum granulosum, which were generally thicker and characterized by a seemingly more highly invaginated cell surface (Figure 1a,c; Fig S1). This stands in contrast both to chemically fixed epidermis where the lower part of the stratum corneum is electron transparent and the upper part, more electron dense, and, however less pronounced, to freeze-substituted epidermis, where the corneocyte transparency increases in the upper part (64Pfeiffer S. Vielhaber G. Vietzke J.-P. Wittern K.-P. Hintze U. Wepf R. High-pressure freezing provides new information on human epidermis: Simultaneous protein antigen and lamellar lipid structure preservation. Study on human epidermis by cryoimmobilization.J Invest Dermatol. 2000; 114: 1030-1038Crossref PubMed Scopus (61) Google Scholar). Download .jpg (.1 MB) Help with files Figure S1The ultrastructure of vitreous native stratum corneum is approximately homogenous throughout its thickness dimension. Low-magnification cryo-transmission electron micrograph of vitreous section of native human stratum corneum. Note the approximately homogenous corneocyte density, size, and form throughout the stratum corneum, with the exception of the lowermost corneocytes that are generally larger and characterized by a seemingly more highly invaginated cell surface (lower right corner). Electron-dense spot corresponds to surface ice contamination (white asterisk). Wave-like diagonal pattern in the upper right corner is due to section compression during cutting. Open white double-arrow: section cutting direction. Section thickness ∼50 nm. Scale bar 1.0 μm. In conventional resin-embedded human forearm epidermis, the corneocytes were characteristically inhomogenously stained and the extracellular space appeared largely empty (Figure 1b,d). Furthermore, the rich variety of cytoplasmic organelles and multigranular structures present in the stratum corneum/stratum granulosum transition (T) cell cytoplasm of vitreous epidermis (Figure 1c, white arrows) were partly replaced by empty space in resin-embedded epidermis (Figure 1d, black asterisk). Consequently, cytoplasmic structures responsible for the formation of the stratum corneum keratin intermediate filament network may partly, or almost entirely, be absent in conventionally fixed resin-embedded epidermal samples. At high magnification (Figure 2), corneocyte keratin intermediate filaments appeared in vitreous epidermal sections as ∼7.8 nm (median; range 7.3–8.3 nm, n=20) (measured as 2 × peripheral to central subfilament center-to-center distance in a direction perpendicular to the section cutting direction; n=number of measurements performed) wide electron-dense structures with a median filament center-to-center distance of ∼16 nm (median; range 12–18 nm, n=20), embedded in a comparatively electron lucent matrix (A,B). In perpendicular section planes, the electron density pattern corresponding to the subfilamentous intermediate filament architecture consisted of one axial subfilament surrounded by an undetermined number of peripheral subfilaments, occasionally being reminiscent of a quasi-hexagonal arrangement of groups of ∼six electron dense ∼1 nm spots surrounding a central electron-dense ∼1 nm spot (A,B, inset box in B). In fact, at closer inspection, the axial subfilament structure could occasionally be distinguished in classical resin-embedded sections (C,D). Here, the corneocyte keratin intermediate filaments appeared as ∼9 nm (median; range 8–11 nm, n=20) wide electron lucent spots embedded in an electron-dense matrix (C). But as no subfilamentous optical density pattern can unambiguously be distinguished in resin-embedded sections and as the optical density of the recorded image here is not directly related to the local density of the biological material of the sample, as it is in vitreous sections, but to the local ability to bind stain, direct comparison of keratin intermediate filament diameter between chemically fixed and cryo-fixed samples is not straightforward. Nonetheless, in the dehydrated resin-embedded sample (C,D) the intermediate filaments were clustered together with diminished interfilament distances when compared with the situation in the fully hydrated native sample (A,B). In viable cell layers of native vitreous epidermis, the keratin intermediate filaments appeared as ∼7.8 nm (median; range 7.3–8.3 nm, n=10) wide electron-dense structures with a median filament center-to-center distance of ∼11 nm (median; range 9–13 nm, n=10) (Figure 3a). As for the stratum corneum (cf. Figure 2), the electron density pattern corresponding to the subfilamentous keratin intermediate filament architecture of viable epidermis consisted of one axial subfilament surrounded by an undetermined number of peripheral subfilaments (A, inset). Consequently, molecular intermediate filament models based on four 8-chain “protofibril” entities (cf.59Parry D.A.D. Steinert P.M. Intermediate filaments: Molecular architecture, assembly, dynamics and polymorphism.Quart Rev Biophys. 1999; 32: 99-187Crossref PubMed Scopus (192) Google Scholar, p 162), or eight 4-chain “protofilament” entities (cf.27Herrmann H. Aebi U. Intermediate filament assembly: Fibrillogenesis is driven by decisive dimer-dimer interactions.Curr Opin Struct Biol. 1998; 8: 177-185https://doi.org/10.1016/S0959-440X(98)80035-3Crossref PubMed Scopus (137) Google Scholar), packing together to form ∼10-nm intermediate filaments with a “hollow” core may, with respect to human epidermal keratin intermediate filament organization, be regarded with some reservation. The possibility remains, however, that the central subfilament density recorded here could arise from an axial alignment of keratin head or tail domains. Keratin function, and in fact the function of all other intermediate filament proteins, is poorly understood (56Omary M.B. Ku N.-O. Liao J. Price D. Keratin modifications and solubility properties in epithelial cells and in vitro.in: Herrmann H. Harris JR. Intermediate Filaments—Subcellular Biochemistry. Plenum Press, New York1998: 105-140Google Scholar). It is, however, widely assumed that the stratum corneum corneocyte keratin network is directly responsible for the mechanical integrity of the epidermis and indirectly responsible for the barrier capacity of the mammalian skin, as it constitutes an indispensable mechanical scaffold for the stratum corneum extracellular lipid matrix (cf.51Norlén L.P.O. Skin barrier structure and function—the single gel-phase model.J Invest Dermatol. 2001; 17: 830-836https://doi.org/10.1046/j.1523-1747.2001.01463.xCrossref Scopus (175) Google Scholar). Further, as keratin is the major non-aqueous component (wt/wt) of stratum corneum and as 90%–100% of the stratum corneum water is thought to be located intracellularly (65Schaefer H. Redelmeier T.E. The Skin Barrier—Principles of Percutaneous Absorption. Karger, Basel1996Google Scholar, p 49), one may presume that keratin also is a major factor (together with filaggrin-derived free amino acids) determining stratum corneum hydration level and water-holding capacity. All these keratin properties depend on the morphology of the stratum corneum keratin intermediate filament network. To date, there are, however, few “hard data” on the structural organization of intermediate filaments (78Van Amerongen H. Kooijman M. Bloemendal M. Transient electric birefringence in the study of intermediate filament assembly.in: Herrmann H. Harris J.R. Intermediate Filaments—Subcellular Biochemistry. Plenum Press, New York1998: 399-421Google Scholar;59Parry D.A.D. Steinert P.M. Intermediate filaments: Molecular architecture, assembly, dynamics and polymorphism.Quart Rev Biophys. 1999; 32: 99-187Crossref PubMed Scopus (192) Google Scholar;58Parry D.A.D. Marekov L.N. Steinert P.M. Subfilamentous protofibril structures in fibrous proteins—cross-linking evidence for protofibrils in intermediate filaments.J Biol Chem. 2001; 276: 39253-39258Crossref PubMed Scopus (40) Google Scholar). The primary fibrous structures in biological materials all belong to a range of polymeric substances whose molecular chains aggregate into regions of (para)crystalline order. Keratin and collagen, two important examples of such fibrous proteins, are characterized by an extremely high elastic resilience, i.e., capacity to absorb and release energy, and strength, i.e., ability to resist a force without too much change in shape. These properties are essentially a function of (i) the (para)crystalline molecular packing and (ii) the three-dimensional higher-order organization of keratin and collagen (cf.82Wainwright S.A. Biggs W.D. Currey J.D. Gosline J.M. MECHANICAL design in Organisms. Edward Arnold (Publishers) Ltd, London1976Google Scholar, p 13, 64). The extraordinary rigidity of keratin allows for maintaining the dimensions of the stratum corneum cellular, and thereby also the extracellular, space unaffected by external (i.e., mechanical) as well as internal (i.e., osmotic) stress. This may in turn be vital, as the continuity of the “crystalline” (or gel) extracellular lipid matrix constituting the skin barrier (24Garson J.-C. Doucet J. Lévêque J.-L. Tsoucaris G. Oriented structure in human stratum corneum revealed by x-ray diffraction.J Invest Dermatol. 1991; 96: 43-49https://doi.org/10.1111/1523-1747.ep12514716Crossref PubMed Scopus (124) Google Scholar;5Bouwstra J.A. Gooris G.S. Salmon-de Vries M.A. Van der Spek J.A. Bras W. Structure of human stratum corneum as a function of temperature and hydration: A wide-angle x-ray diffraction study.Int J Pharmaceut. 1992; 84: 205-216Crossref Scopus (219) Google Scholar;50Norlén L.P.O. Skin barrier formation—the membrane folding model.J Invest Dermatol. 2001; 17: 823-829https://doi.org/10.1046/j.0022-202x.2001.01445.xCrossref Google Scholar) may not, under stress conditions, be preserved otherwise. The epidermis must resist not only tension and compression but also bending, which represent three quite different kinds of forces. Exposure to the environment generally creates the accumulation of a mixture of such limiting strains. Living support systems, like the stratum corneum, therefore tend to be designed as “membrane frameworks” in order to create a force-distribution situation (82Wainwright S.A. Biggs W.D. Currey J.D. Gosline J.M. MECHANICAL design in Organisms. Edward Arnold (Publishers) Ltd, London1976Google Scholar, p 288). A reasonable starting point to understand the structure of a living system is the least-weight idea, as least weight implies the use of minimal material in order to perform a given function. If a structure can be devised in which all parts are in tension or compression at a given load, then that structure will be of minimum weight and by inference also optimally designed. The Michell theorem (44Michell A.G.M. The limits of economy of material in frame-structures.Phil Mag. 1904; S6.8: 589-597Crossref Google Scholar) states that the optimum framework of minimum weight also is the stiffest of all possible frameworks (i.e., has the least deflections per unit stress in all parts of the framework). This is the framework that the stratum corneum must adopt (i.e., when all existing constraints, mechanical as well as non-mechanical, has been complied with) in order to accommodate deflections. In most cases, the tensile structures in organisms can be described as parallel arrays of crystalline polymeric fibers. This is explained by the fact that (i) the Young's modulus (i.e., the ratio between the applied force per unit area and the resulting deformation of a body) of a crystalline polymer often is two to three orders of magnitude greater than that of a liquid crystalline polymer and that (ii) the modulus of oriented crystalline fibers is another order of magnitude greater still (82Wainwright S.A. Biggs W.D. Currey J.D. Gosline J.M. MECHANICAL design in Organisms. Edward Arnold (Publishers) Ltd, London1976Google Scholar, p 64). The disadvantage of unidirectional reinforcement is, however, evident when tensile stress is applied at right angles to the fiber direction. For example, the stratum corneum may simultaneously be under compression, bending, and tension. Such situations limit the use in the stratum corneum of materials that are stiff and strong in one or two dimensions only. Classically, two strategies have been suggested in the search for isotropy of biomechanical properties. The first is to combine a series of unidirectional reinforced laminae with an angular difference between each (e.g., crustacean cuticle;25Gharagozlou-van Ginneken I.D. Bouligand Y. Ultrastructures tegumentaires chez un crustace copepode Cletocampus retrogressus.Tissue Cell. 1973; 5: 413-439Crossref PubMed Scopus (32) Google Scholar). The second is to arrange the fibers in a two- or three-dimensional random orientation (e.g., classical models of stratum corneum keratin filament organization;73Swanbeck G. Macromolecular organisation of epidermal keratin.Acta Derm Venereol (Stockh). 1959; 39: 1-37PubMed Google Scholar;10Brody I. The ultrastructure of the tonofibrils in the keratinization process of normal human epidermis.J Ultrastruct Res. 1960; 4: 264-297Crossref Scopus (119) Google Scholar). The disadvantage of both these strategies is, however, evident as, for a given load, only a fraction of the fibers are doing any real work; the rest are simply adding extra weight and contribute little to the total strength and stiffness of the tissue. There exists, however, a third possibility. If the fibers are arranged isotropically, possibly with isotropically distributed chemical and/or physical attachment points between the fibers, into a cubic (para)crystalline polymer lattice, all fibers would at all loads contribute optimally to the strength and stiffness of the material and thereby distribute impact loads throughout the entire lattice, giving the stratum corneum an optimal strength-to-weight ratio. Given the 50–100 nm thickness of epidermal vitreous cryo-sections, random superposition in three dimensions of ∼8 nm thick keratin filaments would have automatically blurred the cryo-electron micrographs. Single keratin filaments were, however, clearly distinguished everywhere in the corneocytes (Figure 2a,b). Consequently, their three-dimensional distribution cannot be entirely random. Moreover, no preferred keratin filament direction could unambiguously be distinguished (Figure 4a,b). Intriguingly, at medium magnification, the global electron density pattern of the “keratin network” of cryo-electron micrographs (Figure 4a,b) resembled two-dimensional projections of biological membranes with cubic symmetry (Fig S2D; cf. Figure 4d). In the cryo-electron micrographs it seems, however, as if protein entities (i.e., keratin filaments) rather than lipid entities (i.e., membrane bilayers) largely are responsible for the electron contrast (Figure 4). It may consequently be constructive to explore the idea that the “cubic membrane-like” electron density pattern of the “keratin network” not foremostly is produced by a lipid membrane-structure with cubic symmetry, but by a cubic-like rod-packing of keratin intermediate filaments (Figure 5a–c). This notion is further supported by the striking similarity between the cryo-electron density pattern (including its dimension) of the corneocyte matrix (Figure 4a) and that of contrast-inverted cryo-transmission electron micrographs of cubosome monoolein/ethanol/water phases with cubic (or sponge) symmetry (Figure 4e, scale identical to that of B, cubosome side lengths ∼150 nm). A body-centered cubic rod-packing (consisting of four non-intersecting three-fold axes) is tempting to propose as a first-hand alternative as the basic principle behind the structural organization of the corneocyte cytoplasm, as it possesses the greatest possible accumulation of symmetry elements in three-dimensional space (1Andersson S. O'Keeffe M. Body-centred cubic cylinder packing and the garnet structure.Nature. 1977; 267: 605-606Crossref Scopus (22) Google Scholar) (Figure 5a–c)" @default.
• W1979156924 created "2016-06-24" @default.
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• W1979156924 date "2004-10-01" @default.
• W1979156924 modified "2023-10-16" @default.
• W1979156924 title "Stratum Corneum Keratin Structure, Function, and Formation: The Cubic Rod-Packing and Membrane Templating Model" @default.
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