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KRTs

Sunday 8 June 2003

WKP

Definition : Keratins make up the largest subgroup of intermediate filament proteins and represent the most abundant proteins in epithelial cells.

Keratins form one of a family of fibrous structural proteins. It is the key structural material making up hair, horns, claws, hooves, and the outer layer of human skin.

Keratin is also the protein that protects epithelial cells from damage or stress.

Keratin is extremely insoluble in water and organic solvents.

Keratin monomers assemble into bundles to form intermediate filaments, which are tough and form strong unmineralized epidermal appendages found in reptiles, birds, amphibians, and mammals.

The only other biological matter known to approximate the toughness of keratinized tissue is chitin.

The acidic keratins are coded by genes KRT9 (MIM.607606) to KRT19 (MIM.148020). The basic keratins are coded by genes KRT1 (MIM.139350) to KRT8 (MIM.148060), which are located on human chromosome 12.

Keratin filaments are abundant in keratinocytes in the cornified layer of the epidermis; these are proteins which have undergone keratinization. In addition, keratin filaments are present in epithelial cells in general.

For example, mouse thymic epithelial cells (TECs) are known to react with antibodies for keratin 5, keratin 8, and keratin 14. These antibodies are used as fluorescent markers to distinguish subsets of TECs in genetic studies of the thymus.

The human genome encodes 54 functional keratin genes which are located in two clusters on chromosomes 12 and 17. This suggests that they have originated from a series of gene duplications on these chromosomes.

Types

- α-keratins

  • the α-keratins are found in all vertebrates. They form the hair (including wool), stratum corneum, horns, nails, claws and hooves of mammals and the hagfish slime threads.

- b-keratins

  • the harder β-keratins are found only in the sauropsids, that is all living reptiles and birds.
  • They are found in the nails, scales, and claws of reptiles, some reptile shells (Testudines, such as tortoise, turtle, terrapin), and in the feathers, beaks, and claws of birds.
  • These keratins are formed primarily in beta sheets. However, beta sheets are also found in α-keratins.

Additionally, the baleen plates of filter-feeding whales are made of keratin.

Structure

Keratins (also described as cytokeratins) are polymers of type I and type II intermediate filaments, which have only been found in the genomes of chordates (vertebrates , Amphioxus , urochordates ).

Nematodes and many other non-chordate animals seem to only have type VI intermediate filaments, lamins, which have a long rod domain (vs. a short rod domain for the keratins).

They exist as highly dynamic networks of cytoplasmic 10-12 nm filaments that are obligate heteropolymers involving type I and type II keratins.

- Type I (KRT9 (CK9 ) to KRT20 (CK20 )) (smaller and relatively acidic)

- Type II (KRT1 , KRT2 , KRT3 , KRT4 , KRT5 , KRT6 , KRT7 , KRT8 ) (larger and relatively basic-neutral)

This dual nature has a functional relevance because cytokeratin filaments form obligate heteropolymers made of Type I and Type II chains in a 1:1 molar ratio.

The heteromeric nature of the cytokeratin filament subunit is already acquired at the level of the coiled-coil dimer.

Function

The primary function of keratins is to protect epithelial cells from mechanical and non-mechanical stresses that result in cell death.

Other emerging functions include roles in cell signaling, the stress response and apoptosis, as well as unique roles that are keratin specific and tissue specific.

The role of keratins in a number of human skin, hair, ocular, oral and liver diseases is now established and meshes well with the evidence gathered from transgenic mouse models.

Keratin filaments undergo complex regulation involving post-translational modifications and interactions with self and with various classes of associated proteins.

Taxonomy

Currently, at least 20 different polypeptides can be distinguished. CKs feature a number of unique characteristics among IF proteins. Their sequence diversity is not found in other IF proteins.

There are two subtypes of CKs based on sequence homologies:

- Type I (CK-9 to 20) keratins are smaller (40-56.5 kDa) and relatively acidic.

- Type II (CK-1 to 8) are larger (53-67 kDa) and relatively basic-neutral. This dual nature has a functional relevance because cytokeratin filaments form obligate heteropolymers made of Type I and Type II chains in a 1:1 molar ratio. The heteromeric nature of the cytokeratin filament subunit is already acquired at the level of the coiled-coil dimer.

CKs belong to a multigene family of polypeptides. The amino acid sequences for all types of IFs, derived from cDNA clones, reveal only a distant relationship between Type I and Type II CKs and other IF subunits.

Taxonomy

It seems as if genes coding for different IF polypeptides arose from a common ancestral gene, followed by several duplications leading to the early formation of several genes: Type I, II (keratins), III (desmin, vimentin, GFAP, peripherin), IV (neurofilaments, nestin, alpha-internexin) and V (lamins) genes. The multiplicity of related sequences within these classes seems to have arisen from more recent gene duplications.

Cytokeratins structure

CK structures are based on rod-like subparticles. Each single polypeptide chain has amino and carboxy-terminal domains of characteristic size, composition and sequence that are separated by an a-helix-rich domain with a heptad structure. There is a remarkably high amino acid identity in the a-helical rod within Type I and Type II CK sequences, which is not shared by their end domains.

This rod domain contains the most highly conserved sequences and only amino acid substitutions compatible with an a-helical structure have been tolerated. The rod consists of four domains rich in a-helices, referred to as 1A, 1B, 2A and 2B, separated from one another by three regions of b-turns, and a distinct discontinuity near the centre of segment 2B can be found, known as the charge shift region.

These helical parts seem to be nearly constant in size and contain a succession of heptades of the type (a-b-c-d-e-f-g-)n where a and d are usually apolar residues which generate an apolar area on one side of the a-helix. The distribution of charged residues, alternating positive and negative (often in position e or g), results in charged zones along the helix.

This strongly conserved periodicity of about 28 in the distribution of acidic and basic residues along the rod domain, indicates that this pattern is essential in the formation of higher oligomers. The charge shift, in the middle of 2B, is a unique property shared by all cytokeratins.

The non-helical linker segments are constant in size, but their sequences are less conserved except for the very strongly conserved linker (L12) located between the two major helical regions.

The amino- and carboxy-nonhelical termini for both Type I and Type II keratins have subdomains of variable size and sequence (E1 and E2), joined to the rod by subdomains of highly variable repeats (V1 and V2).

In addition, Type II keratins have homologous sequences of conserved size on either side of the rod domain (H1 and H2), whereas Type I keratins only possess a short and variable H1 subdomain.

Two polypeptide chains spontaneously form coiled-coil dimers in solution, by interfacing their respective apolar areas of the a-helix. Short sequences at each end of the rod domain are particularly strongly conserved, and it appears that these regions are critical for assembly, whereas regions in the bulk of the rod seem to be less important.

However, it seems unlikely that simple hydrophobic interactions between residues in the coiled-coil could account for the specificity of keratin pairing seen in vivo and in vitro and it is likely that an intermediate fold facilitates molecular recognition.

Members

KRT1 KRT2A KRT2B KRT3 KRT4 KRT5 KRT6A KRT7 KRT8 KRT9
KRT10 KRT11 KRT12 KRT13 KRT14 KRT15 KRT16 KRT17 KRT18 KRT19
KRT20 KRT21 KRT22 KRT23 KRT24
KRTHs hair keratins
KRTHA1 KRTHA2 KRTHA3A KRTHA3B KRTHA4 KRTHA5 KRTHA6 KRTHA7 KRTHA8
KRTHB1 KRTHB2 KRTHB3 KRTHB4 KRTHB5 KRTHB6
K6IRS1 K6IRS2 K6IRS3 K6IRS4

Pathology

- KRT1 (keratin-1): mutations in bullous congenital ichthyosiform erythroderma)
- KRT2 (keratin-2): mutations in ichthyosis bullosa of Siemens
- KRT8 (keratin-8): mutations in cryptogenetic cirrhosis
- KRT10 (keratin-10): mutations in epidermolytic hyperkeratosis
- KRT16 (keratin-16): mutations in the pachyonychia congenita type 1
- KRT18 (keratin-18): mutations in cryptogenetic cirrhosis
-  pathology of KRTHs (hair keratins)

Expression

Keratin expression in human tissues and neoplasms Keratin filaments constitute type I and type II intermediate filaments (IFs), with at least 20 subtypes named keratin 1-20.

Since certain keratin subtypes are only expressed in some normal human tissues but not others, and vice versa, various tissues have been subclassified according to the pattern of keratin staining.

Simple epithelia generally express the simple epithelial keratins 7, 18, 19, and 20, while complex epithelia express complex epithelial keratins 5/6, 10, 14, and 15.

Pathology of cytokeratins

- see keratinopathies

Diagnostic use in pathology

- cytokeratins / KRTS expression in tumors

Links

- The Intermediate Filament Mutation Database

References

- Owens DW, Lane EB. Keratin mutations and intestinal pathology. J Pathol. 2004 Nov;204(4):377-85. PMID: 15495267

- Lane EB, McLean WH. Keratins and skin disorders. J Pathol. 2004 Nov;204(4):355-66. PMID: 15495218

- Zatloukal K, Stumptner C, Fuchsbichler A, Fickert P, Lackner C, Trauner M, Denk H. The keratin cytoskeleton in liver diseases. J Pathol. 2004 Nov;204(4):367-76. PMID: 15495250

- Owens DW, Lane EB. Keratin mutations and intestinal pathology. J Pathol. 2004 Nov;204(4):377-85. PMID: 15495267

- Rugg EL, Leigh IM. The keratins and their disorders. Am J Med Genet. 2004 Nov 15;131C(1):4-11. PMID: 15452838

- Porter RM, Lane EB. Phenotypes, genotypes and their contribution to understanding keratin function. Trends Genet. 2003 May;19(5):278-85. PMID: 12711220

- Coulombe PA, Omary MB. ’Hard’ and ’soft’ principles defining the structure, function and regulation of keratin intermediate filaments. Curr Opin Cell Biol. 2002 Feb;14(1):110-22. PMID: 11792552

- Ishida-Yamamoto A, Takahashi H, Iizuka H. Lessons from disorders of epidermal differentiation-associated keratins. Histol Histopathol. 2002 Jan;17(1):331-8. PMID: 11813882

- Chu PG, Weiss LM. Keratin expression in human tissues and neoplasms. Histopathology. 2002 May;40(5):403-39. PMID: 12010363

- Stevens HP, Rustin MH. Keratin gene mutations in human skin disease. Postgrad Med J. 1994 Nov;70(829):775-9. PMID: 7529919

- Steinert PM, North AC, Parry DA. Structural features of keratin intermediate filaments. J Invest Dermatol. 1994 Nov;103(5 Suppl):19S-24S. PMID: 7525737

- Smack DP, Korge BP, James WD. Keratin and keratinization. J Am Acad Dermatol. 1994 Jan;30(1):85-102. PMID: 7506275

- Coulombe PA: The cellular and molecular biology of keratins: beginning a new era. Curr Opinion in Cell Biol 1993;5:17-29

- Freedberg IM. Keratin: a journey of three decades. J Dermatol. 1993 Jun;20(6):321-8. PMID: 7688776

- Steinert PM. Structure, function, and dynamics of keratin intermediate filaments. J Invest Dermatol. 1993 Jun;100(6):729-34. PMID: 7684423

- Fuchs E, Coulombe PA. Of mice and men: genetic skin diseases of keratin. Cell. 1992 Jun 12;69(6):899-902. PMID: 1376637