Keratin 1

KRT1
Identifiers
Aliases	KRT1, CK1, EHK, EHK1, EPPK, K1, KRT1A, NEPPK, keratin 1
External IDs	OMIM: 139350; MGI: 96698; GeneCards: KRT1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4ZRY
Gene location (Human) Chr. Chromosome 12 (human) Band 12q13.13 Start 52,674,736 bp End 52,680,407 bp
Gene location (Mouse) Chr. Chromosome 15 (mouse) Band 15 F2|15 57.06 cM Start 101,753,861 bp End 101,759,229 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in skin of thigh vulva skin of arm skin of hip human penis nipple skin of abdomen cervix epithelium gums gingival epithelium Top expressed in lip condyle umbilical cord skin of external ear skin of abdomen human fetus skin of back fossa sexually immature organism cervix More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding structural molecule activity carbohydrate binding structural constituent of skin epidermis signaling receptor activity protein heterodimerization activity Cellular component intermediate filament extracellular matrix blood microparticle plasma membrane keratin filament cytoskeleton membrane nucleus extracellular exosome extracellular region extracellular space cytosol ficolin-1-rich granule lumen cornified envelope collagen-containing extracellular matrix Biological process complement activation, lectin pathway retina homeostasis regulation of angiogenesis negative regulation of inflammatory response response to oxidative stress fibrinolysis establishment of skin barrier keratinization neutrophil degranulation cornification peptide cross-linking protein heterotetramerization Sources:Amigo / QuickGO
Orthologs Databases NCBI: entry; OMA: entry Species Human Mouse Entrez 3848 16678 Ensembl ENSG00000167768 ENSMUSG00000046834 UniProt P04264 P04104 RefSeq (mRNA) NM_006121 NM_008473 RefSeq (protein) NP_006112 NP_032499 Location (UCSC) Chr 12: 52.67 – 52.68 Mb Chr 15: 101.75 – 101.76 Mb PubMed search
Wikidata
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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 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

• Whittock NV, Ashton GH, Griffiths WA, Eady RA, McGrath JA (August 2001). "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. doi:10.1046/j.1365-2133.2001.04327.x. PMID 11531804. S2CID 36140204.
• Langbein L, Schweizer J (2005). Keratins of the human hair follicle. International Review of Cytology. Vol. 243. pp. 1–78. doi:10.1016/S0074-7696(05)43001-6. ISBN 978-0-12-364647-7. PMID 15797458.
• Korge BP, Compton JG, Steinert PM, Mischke D (December 1992). "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. doi:10.1111/1523-1747.ep12614149. PMID 1281859.
• Compton JG, DiGiovanna JJ, Santucci SK, Kearns KS, Amos CI, Abangan DL, et al. (July 1992). "Linkage of epidermolytic hyperkeratosis to the type II keratin gene cluster on chromosome 12q". Nature Genetics. 1 (4): 301–305. doi:10.1038/ng0792-301. PMID 1284546. S2CID 10795444.
• Rothnagel JA, Dominey AM, Dempsey LD, Longley MA, Greenhalgh DA, Gagne TA, et al. (August 1992). "Mutations in the rod domains of keratins 1 and 10 in epidermolytic hyperkeratosis". Science. 257 (5073): 1128–1130. Bibcode:1992Sci...257.1128R. doi:10.1126/science.257.5073.1128. PMID 1380725. S2CID 30648935.
• Chipev CC, Korge BP, Markova N, Bale SJ, DiGiovanna JJ, Compton JG, et al. (September 1992). "A leucine----proline mutation in the H1 subdomain of keratin 1 causes epidermolytic hyperkeratosis". Cell. 70 (5): 821–828. doi:10.1016/0092-8674(92)90315-4. PMID 1381288. S2CID 19725155.
• Dawson SJ, White LA (May 1992). "Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin". The Journal of Infection. 24 (3): 317–320. doi:10.1016/S0163-4453(05)80037-4. PMID 1602151.
• Mansbridge JN, Hanawalt PC (March 1988). "Role of transforming growth factor beta in the maturation of human epidermal keratinocytes". The Journal of Investigative Dermatology. 90 (3): 336–341. doi:10.1111/1523-1747.ep12456286. PMID 2450142.
• Lessin SR, Huebner K, Isobe M, Croce CM, Steinert PM (December 1988). "Chromosomal mapping of human keratin genes: evidence of non-linkage". The Journal of Investigative Dermatology. 91 (6): 572–578. doi:10.1111/1523-1747.ep12477087. PMID 2461420.
• Popescu NC, Bowden PE, DiPaolo JA (May 1989). "Two type II keratin genes are localized on human chromosome 12". Human Genetics. 82 (2): 109–112. doi:10.1007/BF00284039. PMID 2470667. S2CID 8064919.
• Johnson LD, Idler WW, Zhou XM, Roop DR, Steinert PM (April 1985). "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. Bibcode:1985PNAS...82.1896J. doi:10.1073/pnas.82.7.1896. PMC 397440. PMID 2580302.
• Steinert PM, Parry DA, Idler WW, Johnson LD, Steven AC, Roop DR (June 1985). "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. doi:10.1016/S0021-9258(18)88900-1. PMID 2581964.
• Yang JM, Chipev CC, DiGiovanna JJ, Bale SJ, Marekov LN, Steinert PM, et al. (January 1994). "Mutations in the H1 and 1A domains in the keratin 1 gene in epidermolytic hyperkeratosis". The Journal of Investigative Dermatology. 102 (1): 17–23. doi:10.1111/1523-1747.ep12371725. PMID 7507151.
• McLean WH, Eady RA, Dopping-Hepenstal PJ, McMillan JR, Leigh IM, Navsaria HA, et al. (January 1994). "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. doi:10.1111/1523-1747.ep12371726. PMID 7507152.
• Syder AJ, Yu QC, Paller AS, Giudice G, Pearson R, Fuchs E (April 1994). "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. doi:10.1172/JCI117132. PMC 294170. PMID 7512983.
• Kimonis V, DiGiovanna JJ, Yang JM, Doyle SZ, Bale SJ, Compton JG (December 1994). "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. doi:10.1111/1523-1747.ep12412771. PMID 7528239.
• Yoon SJ, LeBlanc-Straceski J, Ward D, Krauter K, Kucherlapati R (December 1994). "Organization of the human keratin type II gene cluster at 12q13". Genomics. 24 (3): 502–508. doi:10.1006/geno.1994.1659. PMID 7536183.
• Peehl DM, Wong ST, Stamey TA (1993). "Vitamin A regulates proliferation and differentiation of human prostatic epithelial cells". The Prostate. 23 (1): 69–78. doi:10.1002/pros.2990230107. PMID 7687781. S2CID 1940715.
• Senshu T, Kan S, Ogawa H, Manabe M, Asaga H (August 1996). "Preferential deimination of keratin K1 and filaggrin during the terminal differentiation of human epidermis". Biochemical and Biophysical Research Communications. 225 (3): 712–719. Bibcode:1996BBRC..225..712S. doi:10.1006/bbrc.1996.1240. PMID 8780679.
• Steinert PM, Marekov LN (January 1997). "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. doi:10.1074/jbc.272.3.2021. PMID 8999895.