Research
- Our Main Objectives
- Introduction to Keratin Genes and Proteins
- Assembly and Organization of Keratin Filaments
- Keratins fulfill Multiple Roles in Skin and other Epithelia
- Keratin Gene Expression in Epidermis: Basic Principles and Disease Associations
- Introduction to Skin Epithelia
- Figure 1 - Introduction to Keratins
- Table 1 - Keratin-based, Inherited Skin Bullous Disease Affecting Primarily the Epidermis
Introduction to Keratin Genes and Proteins
Keratins are the most abundant structural proteins in the cytoplasm of epithelial cells, in which they form a network of 10-12 nm wide intermediate filaments (IFs) (see Figure below). Keratin proteins are encoded by a large family of conserved genes, numbering ~54 in the human genome, which partition to either the type I and type II subgroupings of IF-encoding genes. There are 28 type I (K9-K28; K31-K40) and 26 type II (K1-K8; K71-K86) keratin genes, each coding for one polypeptide [J. Schweizer et al., J. Cell Biol. 2006]. Type I proteins tend to be smaller (40-64 kDa) and more acidic (pI ~4.7-6.1) than the larger (52-70 kDa) and basic-neutral (pI ~5.4-8.4) type II proteins. Keratin polymerization obligatorily begins with the formation of coiled-coil heterodimers involving one type I and one type II proteins. This requirement underlies the pairwise transcriptional regulation of keratin genes in vivo. The regulation of keratin genes, individually or as pairs, ultimately depends upon the type of epithelia, stage of cellular differentiation, and "context" (such as normal tissue turnover or disease). As such, keratin genes and proteins provide an unparalleled molecular handle to track the status of epithelial cells in health and disease.
In homo sapiens, the functional type I and type II keratin genes are clustered on the long arms of chromosomes 17 and 12, respectively, the sole exception being the K18 locus, which is located next to its partner gene K8. Whole genome sequencing has confirmed that the genomic organization, sequence, and regulation of keratin genes is highly conserved among mammals. When considering keratin primary structure in light of the physical organization of keratin genes in mammalian genomes, one infers that a hierarchical sequence of gene duplication and specialization took place during evolution. Along with their relatively large number, the promiscuity with which type I and II keratin proteins pair up and polymerize with one another generates a tremendous diversity in the surface chemistry of keratin filaments in living cells. How this phenomenon relates to their function in epithelial cells remains underappreciated, and represents an issue of great interest to our laboratory.
