Keratin, a fibrous protein crucial to the structural integrity of various animal tissues, plays a vital role in forming tough structures such as hair, feathers, nails, and horns. It is categorized based on tissue origin and sulfur content, with soft keratins having lower sulfur content and hard keratins, found in hair and claws, containing more sulfur, resulting in a stronger structure. Keratins are classified into two types: acidic Type I and neutral-to-basic Type II, further divided into Type I a and b, and Type II a and b. The initial step in keratin formation involves the alignment of type I and type II keratin polypeptides to create a heterodimer, which then aggregates into higher-order structural units. This article will explore the distinctions between alpha and beta keratins, their properties, functions, and significance in various organisms.
Keratin is a family of fibrous structural proteins known for their toughness and insolubility. They are the main structural component of various epidermal appendages, protecting epithelial cells from damage and stress. Originating from the embryonic epidermis, the hair follicle evolves into one of the most complex structures in the human body, comprising 7-8 distinct tissue sections. Keratin filaments are integrated into desmosomes and hemidesmosomes, contributing to cell-to-cell stability and attachment to the basement membrane and connective tissue within an epithelium.
Keratins are divided into two major groups:
Keratins are further categorized into acidic type I and basic-to-neutral type II cytokeratins. The intermediate filament network is formed by the necessary pairing of equal amounts of type I and type II keratins.
The structural differences between α-keratins and β-keratins account for their distinct mechanical properties and biological roles.
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Alpha-keratins are characterized by their alpha-helical structure. The polypeptide chains are coiled into a tight helix, stabilized by hydrogen bonds. These helices then intertwine to form coiled-coil dimers, which further assemble into protofilaments, intermediate filaments, and eventually, macrofibrils. Similar to other intermediate filament subunit proteins, a prevalent secondary structure exists: a well-preserved, central alpha-helical domain made up of four coiled-coil segments along with non-helical end-terminal domains that vary in sequences and lengths. This hierarchical structure provides α-keratins with elasticity and flexibility, making them suitable for tissues that undergo stretching and bending, such as hair and skin.
The arrangement of hair's layers-the cortex and cuticle-forms a hierarchical structure. The cortex primarily consists of a keratin coiled-coil protein phase. These proteins assemble into intermediate filaments, progressively forming larger fibers. Enveloping the hair is the cuticle, composed of deceased cells. X-ray data from various samples consistently reveal specific signals associated with the coiled-coil keratin phase, intermediate filament development in the cortex, and the cell membrane complex.
Beta-keratins, on the other hand, have a beta-sheet structure. The polypeptide chains are arranged in a zig-zag pattern, forming pleated sheets that are stacked upon each other. These sheets are connected by hydrogen bonds, creating a rigid and strong structure. This arrangement provides β-keratins with exceptional strength and resistance to deformation, ideal for tissues that require hardness and protection, such as scales and claws.
Alpha and beta keratins serve distinct functions in different organisms, reflecting their structural properties.
In mammals, α-keratins are essential for:
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Beta-keratins provide unique advantages to reptiles and birds:
The hair shaft is majorly composed of hair keratins and their associated proteins (KRTAPs). KRTAPs are products of diverse gene families resulting from gene duplication events in their evolutionary history. These genes are typically small, comprising a single exon less than 1,000 base pairs long. Over the last decade, numerous KRTAP genes have been identified across mammals, including humans. They are categorized into three groups based on their amino acid composition: high sulfur (with <30 mol% cysteine), ultrahigh sulfur (>30 mol% cysteine), and high glycine/tyrosine. Hair keratins form intermediate filaments (KIFs) within trichocytes, specialized cells that contribute to hair formation. As these cells move upward in the cortex, KIFs aggregate, surrounded by a space called the matrix. KRTAPs, also known as KAPs, are a significant part of this matrix between KIFs.
Recent attention has been drawn to the remarkable wound-healing capabilities and excellent biocompatibility of keratin derived from human hair. While recombinant keratin proteins produced via recombinant DNA technology offer higher purity compared to extracted keratin, their wound-healing properties have remained unclear. Two recombinant trichocyte keratins-human type I hair keratin 37 and human type II hair keratin 81-were expressed using a bacterial expression system and subsequently forming recombinant keratin nanoparticles (RKNPs) through ultrasonic dispersion. It has been revealed that RKNPs significantly boosted cell proliferation and migration in laboratory settings. Moreover, when applied to dermal wounds in vivo, RKNPs facilitated improved wound healing, leading to enhanced epithelialization, vascularization, collagen deposition, and remodeling. Importantly, tests for in vivo biocompatibility showed no signs of systemic toxicity.
In vivo haemostasis efficacy studies were conducted using rat models of liver puncture and femoral artery injury. For both models, K37 and K81 (10 mg) were applied to cover the wound areas. In the liver puncture model, bleeding time significantly decreased with recombinant K37 (approximately 38 s) and K81 (approximately 40 s) compared to the vehicle alone (approximately 170 s, p < .01), with notably reduced total blood loss (p < .01). Furthermore, in the femoral artery injury model, the recombinant keratin proteins significantly reduced bleeding time compared to the control group (approximately 50 s vs. 270 s). Notably, K37 and K81 exhibited stronger haemostatic effects than extracted keratins (approximately 80 s) in treating rat liver injury. Additionally, the recombinant keratin proteins demonstrated a robust capacity to promote the formation of a fibrin clot at the injury site, effectively stopping the bleeding.
Keratin constitutes a large multigene family known as cytokeratins. These cytokeratins are differentially expressed across various epithelial types and have been extensively studied as markers for breast cancer. They are categorized into acidic type I and basic-to-neutral type II cytokeratins. KRT81, a type II hair keratin, is a major hair protein expressed in the hair cortex. Interestingly, despite being typically associated with hair structures, KRT81 expression has been observed in the SKBR3 human breast cancer cell line and metastatic lymph nodes of breast carcinomas, but not in normal breast epithelial cells. This presents the first evidence of complete KRT81 expression in both normal breast epithelial cells and breast cancer cells.
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The relationship between diet and keratin production is complex and not fully understood. Some argue that a diet rich in beta-keratin could lead to stronger offspring in reptiles, while others suggest that genetic factors primarily determine the presence or absence of keratin structures. The idea that feeding adult breeders a diet rich in beta-keratin would result in stronger offspring has been considered.
Keratin synthesis requires amino acids, the building blocks of proteins. Therefore, a balanced diet with adequate protein is essential for keratin production. However, whether dietary intake of pre-formed keratin directly influences the quality and quantity of keratin structures is debatable.
Genetic defects can prevent an animal from creating keratin structures, regardless of diet. Translucent veileds or leatherback beardies will not get their scales back no matter what you do. It's permanent.
The presence of different keratin types in various species reflects evolutionary adaptations to specific environments and lifestyles. The emergence of beta-keratin in reptiles and birds allowed for the development of specialized structures that enhanced survival and reproductive success.
Environmental factors can influence the expression and modification of keratin genes. For example, species at higher elevation may need better protection from UV rays such as UVC and reptile skin may have also adapted for this purpose.
Historically, the term ‘keratin’ stood for all of the proteins extracted from skin modifications, such as horns, claws and hooves. Subsequently, it was realized that this keratin is actually a mixture of keratins, keratin filament-associated proteins and other proteins, such as enzymes. Keratins were then defined as certain filament-forming proteins with specific physicochemical properties and extracted from the cornified layer of the epidermis, whereas those filament-forming proteins that were extracted from the living layers of the epidermis were grouped as ‘prekeratins’ or ‘cytokeratins’. Currently, the term ‘keratin’ covers all intermediate filament-forming proteins with specific physicochemical properties and produced in any vertebrate epithelia.
Similarly, the nomenclature of epithelia as cornified, keratinized or non-keratinized is based historically on the notion that only the epidermis of skin modifications such as horns, claws and hooves is cornified, that the non-modified epidermis is a keratinized stratified epithelium, and that all other stratified and non-stratified epithelia are non-keratinized epithelia. At this point in time, the concepts of keratins and of keratinized or cornified epithelia need clarification and revision concerning the structure and function of keratin and keratin filaments in various epithelia of different species, as well as of keratin genes and their modifications, in view of recent research, such as the sequencing of keratin proteins and their genes, cell culture, transfection of epithelial cells, immunohistochemistry and immunoblotting. Recently, new functions of keratins and keratin filaments in cell signaling and intracellular vesicle transport have been discovered. It is currently understood that all stratified epithelia are keratinized and that some of these keratinized stratified epithelia cornify by forming a Stratum corneum. The processes of keratinization and cornification in skin modifications are different especially with respect to the keratins that are produced. Future research in keratins will provide a better understanding of the processes of keratinization and cornification of stratified epithelia, including those of skin modifications, of the adaptability of epithelia in general, of skin diseases, and of the changes in structure and function of epithelia in the course of evolution.
When we started to survey, collect and organize the current knowledge on keratins (unless mentioned otherwise, hereafter the term ‘keratins’ refers to keratin proteins) and keratin filaments for the invited review of keratins in soft-keratinized epidermis and epithelia, we soon realized that such a study would lead to a greater understanding only if the keratins were discussed as integral elements of cells, tissues and organs. As an analogy, a review of collagen would also make sense only within the context of connective tissue structures (Wang, 2006). Corneous, or horny, tissues have a long history of interest due to their economic, practical and emotional value. For example, the sheaths of horns have been fashioned into drinking vessels; mammalian fur has been used for clothing; the skin of reptiles has been manufactured into leather for clothing and pouches; mammalian hair has been used to make felt or to spin yarn for weaving and knitting; feathers have been used for various bedding materials and clothing; baleen has been used as whalebone in the fashion industry; ‘tortoise shell’ has been used for making combs and decorative objects; and hooves of farm animals have been used as slowly decaying fertilizers (Gupta & Ramnani, 2006; Thys & Brandelli, 2006). Keratin-rich tissues are studied for their economic importance in the wool industry, for cosmetics and dermatology (Er Rafik et al. 2004). Furthermore, the health of the hooves of farm and draft animals is of crucial economic importance to large animal producers and forms the basis of a longstanding interest in veterinary medicine concerning the structure and function of keratinized and cornified tissues.
Corneous tissues hold a special place among the tissues of vertebrates as they cover the surface of animals and, thereby, represent the interface between an organism and its environment (Wu et al. 2004). Hence, both the underlying connective tissues of the organism and the environment directly influence these corneous tissues and the effects of these influences can often be observed in vivo (Homberger & Brush, 1986). Despite the great variety in appearance, it was recognized by early comparative anatomists that structures as diverse as hairs, feathers, hooves and baleen consist of a similar substance, which was called ‘horn’ or ‘keratin’ (Siedamgrotzky, 1871; Tullberg, 1883). Subsequently, it was recognized that corneous tissue can be relatively soft and pliable or relatively hard and stiff (Boas, 1881) and that these different properties can be correlated to different types of keratin molecules within the cells [e.g. α- and β-keratins, acidic vs. basic, soft vs. hard, various molecular weights (MWs)] (Fraser et al. 1972). As more data have become available, it has also become clear that the composition of keratins within each category of corneous tissue is more diverse than previously assumed (Moll et al. 1982; Schweizer et al. 2006), with various gradations between the categories (Hesse et al. 2004).
Vertebrate tissues are traditionally divided into two major categories: (1) epithelial tissues of ectodermal or endodermal origin and with little intercellular substances (i.e. intercellular cementing substance); and (2) mesenchymal (connective) tissues of mesodermal origin with a substantial amount of extracellular substances (e.g. glycosaminoglycans, collagen fibers, etc.) (Banks, 1993). However, the distinction between these two categories is not as sharp as some textbooks report and some tissues, such as keratinized tissues, do not fit neatly within this scheme.
Epithelia line surfaces, form glands and act as receptor cells in sensory organs (Fig. 1). Epithelial tissues line internal and external surfaces, such as the external surface of the skin or the internal lining of the intestine. In addition, epithelia line the ducts and secretory units of glands, such as those of the liver or pancreas. Epithelia separate compartments by forming barriers (e.g. blood-urine barrier), regulate the exchange of molecules between compartments (e.g. between intestine and blood) and protect tissues and structures covered by stratified epithelia (e.g. Fig.
Pre- and postnatal development of epithelial tissues. The first epithelia in a vertebrate embryo are simple epithelia such as the trophoblast epithelium or the epithelium of the vitelline sac. Epithelial tissues are derivatives of all three germ layers, i.e. the ectoderm, mesoderm and endoderm. All stratified epithelia start as simple epithelia and stratify as well as differentiate during the embryonic, fetal development and even postnatal development. The structures of epithelia reflect their various functions, e.g. semipermeable or protective barrier.
Epithelial tissues consist of squamous, cuboidal, columnar or polyhedral cells that are attached to one another via short cell processes. These cells produce only a small amount of intercellular substances (Banks, 1993). The structure of epithelial tissues varies with its function. Morphological characteristics, such as cell shape and stratification, are the basis for the classification of epithelial tissues (Frappier, 2006). In general, epithelia are distinguished as being simple, transitional or stratified (Fig.
Two types of simple epithelia are distinguished, i.e. single-layered and multi-layered epithelia. In single-layered epithelia, all cells are attached to the basement membrane and extend to the surface of the epithelium (e.g. endothelium, mesothelium, epithelium in the renal tubules and alveoli). In multi-layered epithelia (i.e. pseudostratified epithelia), all cells are in contact with the basement membrane but do not necessarily extend to the surface of the epithelium (e.g. In transitional epithelia, at least some cells attach to the basement membrane and also extend to the surface of the epithelium [e.g. In stratified epithelia, only the basal cells are attached to the basement membrane and only the most superficial of the suprabasal cell layers form the surface of these epithelia. Only the cells in the basal stratum are mitotically active and replenish the loss of cells on the surface of the superficial stratum. In the intermediate stratum of a stratified epithelium, the cells undergo various processes of differentiation, such as keratinization. In the superficial stratum of a stratified, non-cornified epithelium, the cells (i.e. keratinocytes) are living and keratinized but not cornified (e.g. The epithelial cells in the superficial stratum (i.e. the Stratum corneum), the corneocytes, are cornified and dead.
Cornification requires the previous keratinization of cells, including the addition of a proteinaceous layer (i.e. the cornified envelope) on the cytoplasmic surface of the cell membrane. In general, two types of stratified-cornified epithelia are distinguished, namely the soft-cornified epithelia (e.g. the epidermis), and the hard-cornified epithelia (e.g. The suprabasal cell layers include a Stratum granulosum characterized by the presence of basophilic keratohyalin granules, which store the KFAPs that are synthesized by the keratinizing cells. In the process of soft cornification, the KFAPs form a filament-matrix complex and a proteinaceous cellular envelope on the inside of the cell membrane. The superficial cornified cells of stratified non-modified soft-cornified epithelia (e.g. epidermis) desquamate continuously and readily, whereas those of modified stratified soft-cornified epithelia (e.g. In stratified hard-cornified epithelia, the suprabasal cell layers do not include a Stratum granulosum (e.g. cortex of hair, plate of the human fingernail, cornified sheath of a cat claw, cornified sheath of a bird beak, wall of the horse hoof, mechanical filiform papillae of the tongue, palatal rugae, baleen plates of mysticete whales).
There are three types of filaments, each with specific properties, which interact with one another in the formation of the cytoskeleton of epithelial cells (Frappier, 2006). Microfilaments are the smallest filaments of the cytoskeleton with a diameter of 7 nm. They are assembled from globular actin molecules, which join to form filamentous actin by using energy from adenosine triphosphate or guanosine triphosphate. Two filamentous actin molecules then combine into a helical microfilament. Microfilaments are polarized so that while one end is elongated by the addition of more filamentous actin molecules, the opposite end is disassembled. Therefore, actin microfilaments can act as conveyor belts for micro-motor molecules, such as myosin. Actin filaments are anchored via actin-binding proteins (e.g.
Microtubules are the largest filamentous structures of the cytoskeleton with a diameter of about 20 nm. They are assembled from α- and β-tubulin molecules, which form heterodimers. These heterodimers are assembled using energy from guanosine triphosphate to form protofilaments, which in turn are combined to form a hollow microtubule. Microtubules are polarized and, thus, can act as conveyor belts for micro-motor molecules (e.g. dynein, kinesin) similar to microfilaments. Microtubule formation is initiated by so-called microtubule-organizing centers, such as the basal bodies in kinocilia or the centrosomes involved in the formation of the spindle apparatus of cells. The network of microtubules is stabilized within a cell by the surrounding microfilaments and intermediate filaments.
Intermediate filaments differ fundamentally from microfilaments and microtubules. Unlike microfilaments and microtubules, intermediate filaments can aggregate into bundles of varying diameter, ranging from 7 to 12 nm. Intermediate filaments are not polarized. Therefore, intermediate filaments are not involved in intracellular transport but serve as a scaffold for the cytoskeleton. Recently, however, keratin filaments in mammals have been suggested to be involved in the transport of melanosomes from their site of endocytosis in the cell periphery to the cell center (Planko et al. 2007). Keratins that form intermediate filaments are expressed exclusively in epithelial cells sensu lato (Moll et al. 1982; Steinert, 2001), regardless of the germ layer origin of these cells. In non-epithelial cells, there are various types of intracellular intermediate filaments, including desmin (in myogenic cells), vimentin (in fibroblasts and fibrocytes), lamin (in cell nuclei) and neurofilaments (in neuronal cells) (Moll et al. 1982). In addition, cells in connective tissues (e.g. fibroblasts, chondroblasts) produce extracellular fibers, such as collagen.
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