Biology:Keratin 1

Short description: Protein found in humans

Generic protein structure example

Keratin 1 (K1) is a Type II intermediate filament (IFs) of the intracytoplasmatic cytoskeleton. It is co-expressed with and binds to Keratin 10, a Type I keratin, to form a coiled coil heterotypic keratin chain which then combine to constitute intermediate filaments. Keratin 1 and Keratin 10 are specifically expressed in the spinous and granular layers of the epidermis. Here, they are involved in both developing a physical barrier and various immune functions. Mutation of the protein causes forms of bullous congenital ichthyosiform erythroderma, and over expression is related to various cancers as it acts as a tumor-associated marker.

Structure

Keratin 1 is a type of fibrous protein of the keratin family and is primarily involved in the formation of rope-like intermediate filaments. More specifically, it is a Type II intermediate filament, meaning it is has a generally larger and neutral-basic structure compared to the small and acidic Type I counterparts. The rod-like structure of K1 consists of a coiled-coil central domain, which is surrounded by flexible, glycine-rich loops at the terminal ends. In all, K1 consists of 644 amino acids (aa) with the internal central domain consisting of four coiled segments made up of 313 amino acids, the 180 aa N-terminal head, and 151 aa C-terminal tail. These tail regions, rich in glycine loops, are known to assist in the assembly of mature intermediate filaments via head-to-tail attachment of K1 units. Additionally, low-complexity aromatic-rich kinked segments (LARKS), found at the tail ends, take on a β-sheet structure, which further assists in this head-to-tail linkage.

Type II cytokeratins, like K1, are clustered in a region of chromosome 12q13.13. Specifically, Keratin 1 is generated from the KRT1 gene. The protein has a molecular weight of roughly 66 kDa and an isoelectric point of roughly 8.3, further confirming that the protein is basic.

Keratin 1 often dimerizes with Keratin 10 to create a parallel heterodimer in a process driven by hydrophobic interactions. However, polarization of charges between the coils and acid-base interactions also play a role. The dimers have three general structural components: a basic N-terminus, an acidic shaft, and an acidic C-terminus. Primarily due to hydrophobic interactions, these dimers then go on to tetramerize in an antiparallel fashion, from which they can form into intermediate filament structures. Due to the antiparallel structure of the tetramers, the basic nature of the N-termini is over-powered and eliminated. Therefore, when considering the electrostatic imbalance of the dimers, the tetramer takes on an acidic overall nature. The four key structures in the tetramerization from the K1/K10 heterodimer to the K1/K10 tetramer are the K1 hydrophobic pocket, K10 hydrophobic stripe, K1 interaction residues, and K1 anchoring knob. From these structures, the most important mechanism in tetramerization is that of the K1-hydrophobic pocket enveloping and binding to the K1 anchoring knob. Overall, the intermediate filament assembly from K1 and K10 is driven mainly by hydrophobic interactions in the knob-pocket mechanism.

Function

The general formation of keratin intermediate filament is as follows: a type I keratin and a type II keratin bind to create a parallel heterodimer, which then uses a matching pair to create an antiparallel tetramer with two of each type. The tetramers go on to combine into a protofibril, which then combine with other protofibrils to make the final keratin intermediate filament.

Therefore, K1, being a type II keratin protein, combined with the type I K10 serve as base units of specific intermediate filaments. This K1/K10 intermediate filament final product is a structural component of the suprabasal (spinous and granular) layer cells in the epidermis. While its most common type I pair in the epidermis is K10, in the palms and soles of the feet, it can pair with Keratin 9 (K9). The epidermis is critical in the body's integumentary system and is involved in mechanical protection, water balance, and immune homeostasis.

Regarding its role in epidermal structural stability, K1 and K10 tetramers are the primary component in the cytoskeleton on the suprabasal keratinocytes. In contrast, basal layer keratinocytes express little to no Keratin 1. More specifically, upregulation of K1 and K10 in the keratinocytes induces filaggrin and cornified envelope proteins. K1 then crosslinks with these proteins and complex lipids to form the cornified envelope. The cornified envelope is the main protective structure in the epidermis and replaces plasma membranes in keratinocytes. It is a protein layer consisting of keratins like K1, K10, and the proteins mentioned. The overall barrier of the epidermis is completed with the immune function of Langerhans cells. The importance to the skin barrier is seen in dysfunctional K1 cases, where the skin erodes and becomes blistered.

Beyond its role in providing structural toughness to the epidermis, K1 is also involved in the innate immune system of the epithelia that it is found in. It plays a role in local and systemic inflammation pathways and can even promote apoptosis in the smooth muscle of blood vessels affected with atherosclerosis. It acts as an inhibitor to the activation of the proinflammatory cytokine interleukin-18 (Il-18) in the case of an intact skin barrier. It works in tandem with Keratin 17 (K17), which induces inflammatory signaling pathways and protein synthesis in the case of a challenged skin barrier via injury, cancer, or irritants. Therefore, in a chronic or acute challenge to the skin barrier, K1 is down-regulated and K17 is up-regulated.

Last, K1 and its dimer partner, K10, are found in the sweat gland ducts of the skin. However, they are not present in any parts of a hair unit, like the follicle or the hair itself.

Related diseases

With its structural properties, Keratin 1 is involved in cell growth and proliferation. Therefore, its overexpression can be used as a marker for cancer in events like tumorigenesis and apoptosis. Overexpression of K1 has been witnessed in various forms of cancer, such as triple negative breast cancer, Nasopharyngeal carcinoma, and neuroblastomas. These cancerous cells display cell-surface keratins that are modified and are likely involved in receptor-mediated endocytosis and evasion of the immune system. Therefore, current research is aiming to use this overexpressed cell-surface K1 as a receptor for targeted drug delivery in cutting-edge cancer treatment. Additionally, K1 is overexpressed in cells that are experiencing oxidative stress, meaning its overexpression could have therapy target potential in other diseases as well.

Mutations in KRT1, the gene encoding Keratin 1, have been associated with variants of the disease bullous congenital ichthyosiform erythroderma. Often, this disease presents with systemic blistered skin and then develops into thick and ichthyotic skin, due to fragmentation of the suprabasal layer where K1 is critical in the structure. Additionally, the skin becomes hyperproliferative, with rapid growth, and hyperkeratotic. Mutations in KRT10 have also been associated with bullous congenital ichthyosiform erythroderma; however, in patients with KRT10 mutations the palms and soles are spared. This difference is likely due to K9, rather than K10, being the major binding partner of K1 in acral (palm and sole) keratinocytes.

Interactions

Keratin 1 has been shown to interact with desmoplakin and PRKCE.

See also

• 34βE12

Further reading

• "New mutations in keratin 1 that cause bullous congenital ichthyosiform erythroderma and keratin 2e that cause ichthyosis bullosa of Siemens". The British Journal of Dermatology 145 (2): 330–335. August 2001. doi:10.1046/j.1365-2133.2001.04327.x. PMID 11531804. 
• "Keratins of the human hair follicle". International Review of Cytology 243: 1–78. 2005. doi:10.1016/S0074-7696(05)43001-6. ISBN 978-0-12-364647-7. PMID 15797458. 
• "The two size alleles of human keratin 1 are due to a deletion in the glycine-rich carboxyl-terminal V2 subdomain". The Journal of Investigative Dermatology 99 (6): 697–702. December 1992. doi:10.1111/1523-1747.ep12614149. PMID 1281859. 
• "Linkage of epidermolytic hyperkeratosis to the type II keratin gene cluster on chromosome 12q". Nature Genetics 1 (4): 301–305. July 1992. doi:10.1038/ng0792-301. PMID 1284546. 
• "Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis". Science 257 (5073): 1128–1130. August 1992. doi:10.1126/science.257.5073.1128. PMID 1380725. Bibcode: 1992Sci...257.1128R. 
• "A leucine----proline mutation in the H1 subdomain of keratin 1 causes epidermolytic hyperkeratosis". Cell 70 (5): 821–828. September 1992. doi:10.1016/0092-8674(92)90315-4. PMID 1381288. 
• "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin". The Journal of Infection 24 (3): 317–320. May 1992. doi:10.1016/S0163-4453(05)80037-4. PMID 1602151. 
• "Role of transforming growth factor beta in the maturation of human epidermal keratinocytes". The Journal of Investigative Dermatology 90 (3): 336–341. March 1988. doi:10.1111/1523-1747.ep12456286. PMID 2450142. 
• "Chromosomal mapping of human keratin genes: evidence of non-linkage". The Journal of Investigative Dermatology 91 (6): 572–578. December 1988. doi:10.1111/1523-1747.ep12477087. PMID 2461420. 
• "Two type II keratin genes are localized on human chromosome 12". Human Genetics 82 (2): 109–112. May 1989. doi:10.1007/BF00284039. PMID 2470667. https://zenodo.org/record/1232401. 
• "Structure of a gene for the human epidermal 67-kDa keratin". Proceedings of the National Academy of Sciences of the United States of America 82 (7): 1896–1900. April 1985. doi:10.1073/pnas.82.7.1896. PMID 2580302. Bibcode: 1985PNAS...82.1896J. 
• "Amino acid sequences of mouse and human epidermal type II keratins of Mr 67,000 provide a systematic basis for the structural and functional diversity of the end domains of keratin intermediate filament subunits". The Journal of Biological Chemistry 260 (11): 7142–7149. June 1985. doi:10.1016/S0021-9258(18)88900-1. PMID 2581964. 
• "Mutations in the H1 and 1A domains in the keratin 1 gene in epidermolytic hyperkeratosis". The Journal of Investigative Dermatology 102 (1): 17–23. January 1994. doi:10.1111/1523-1747.ep12371725. PMID 7507151. 
• "Mutations in the rod 1A domain of keratins 1 and 10 in bullous congenital ichthyosiform erythroderma (BCIE)". The Journal of Investigative Dermatology 102 (1): 24–30. January 1994. doi:10.1111/1523-1747.ep12371726. PMID 7507152. 
• "Genetic mutations in the K1 and K10 genes of patients with epidermolytic hyperkeratosis. Correlation between location and disease severity". The Journal of Clinical Investigation 93 (4): 1533–1542. April 1994. doi:10.1172/JCI117132. PMID 7512983. 
• "A mutation in the V1 end domain of keratin 1 in non-epidermolytic palmar-plantar keratoderma". The Journal of Investigative Dermatology 103 (6): 764–769. December 1994. doi:10.1111/1523-1747.ep12412771. PMID 7528239. 
• "Organization of the human keratin type II gene cluster at 12q13". Genomics 24 (3): 502–508. December 1994. doi:10.1006/geno.1994.1659. PMID 7536183. 
• "Vitamin A regulates proliferation and differentiation of human prostatic epithelial cells". The Prostate 23 (1): 69–78. 1993. doi:10.1002/pros.2990230107. PMID 7687781. 
• "Preferential deimination of keratin K1 and filaggrin during the terminal differentiation of human epidermis". Biochemical and Biophysical Research Communications 225 (3): 712–719. August 1996. doi:10.1006/bbrc.1996.1240. PMID 8780679. 
• "Direct evidence that involucrin is a major early isopeptide cross-linked component of the keratinocyte cornified cell envelope". The Journal of Biological Chemistry 272 (3): 2021–2030. January 1997. doi:10.1074/jbc.272.3.2021. PMID 8999895.