Structure and functions of keratin proteins in simple, stratified, keratinized and cornified epithelia

Abstract

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. This review focuses on keratins and keratin filaments in mammalian tissue but keratins in the tissues of some other vertebrates are also considered.

Fig. 1

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.

Fig. 2

Schematic depictions of the secondary structure of a keratin molecule (a), the heterodimer (b) and the different modes of alignment of heterodimers to form tetramers (c). (a) The X-ray diffraction analyses of purified keratins as well as the analysis of the sequence of the amino acids in the chain of a keratin revealed the secondary structure of keratins molecule. This molecule forms three domains, the head domain at the N-terminal end of the molecule, the central rod domain and the tail domain at the C-terminal end of the molecule. The head domain of a keratin molecule consists of three subdomains, i.e. the end subdomain (E1), the variable subdomain (V1) in the middle and the homologous subdomain (H1). The central rod domain consists of four α-helical subdomains, which are connected by β-turn linker regions (L). The subdomains 1A and 1B are connected via linker L1 and the subdomains 2A and 2B are connected via linker L2. The subdomains 1B and 2A of the rod domain are connected via the linker L12 (linker ‘one-two’). The N-terminal part of the subdomain 1A is called helix initiating motive (h i m) and the C-terminal part of the subdomain 2B functions as a helix terminating motif (h t m). In addition, the α-helix of this subdomain 2B in the rod domain of a keratin molecule is interrupted by a stutter (st). The subdomains (H2, V2, E2) of the tail domain of a keratin molecule are similar to those in the head domain. (b) One acidic keratin molecule, i.e. a type I keratin, and one basic keratin molecule, i.e. a type II keratin, align in parallel to form a heterodimer. (c) Two of the same heterodimers of keratins associate in antiparallel and staggered alignment modes (A₁₁, A₂₂, A₁₂) or in the end-to-end alignment mode A_CN to form a tetramer (see section ‘Quaternary structure of keratins’ for details).

Fig. 3

Ectodermal stratified epithelia and the keratins produced in the basal and suprabasal cells. The basal cells of all stratified epithelia produce K5 and K14 but the suprabasal cells of stratified epithelia produce specific keratins, which are characteristic of the type of epithelium, e.g. the suprabasal cells of the anterior epithelium of the cornea produce K3/K12.

Fig. 4

The cells in the strata of stratified keratinized vs. stratified keratinized and cornified epithelia: similarities and differences. The Stratum basale of stratified epithelia houses the keratinoblasts, i.e. stem cells and transient amplifying cells as well as undifferentiated keratinocytes. As soon as the keratinocytes are pushed upwards by the following cell generation thereby losing contact with the basal lamina, they begin the specific differentiation process and produce specific keratins such as K1 and K10. The cells of the keratinizing and cornifying epidermis and of its derivatives, e.g. hair and nail, die in a programmed cell death and become the corneocytes in the superficial Stratum corneum. In contrast, the keratinocytes of keratinized, non-cornifying epithelia are viable cells forming the superficial stratum. These keratinized, non-cornifying epithelia, e.g. epithelia of the oral and vaginal mucosa, can cornify in reacting to changes in mechanical or hormonal signals.