Keratin 5, also known as KRT5, K5, or CK5, is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that is encoded in humans by the ''KRT5''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
It
dimerizes
In chemistry, dimerization is the process of joining two identical or similar molecular entities by bonds. The resulting bonds can be either strong or weak. Many symmetrical chemical species are described as dimers, even when the monomer is u ...
with
keratin 14
Keratin 14 is a member of the type I keratin family of intermediate filament proteins. Keratin 14 was the first type I keratin sequence determined.
Keratin 14 is also known as cytokeratin-14 (CK-14) or keratin-14 (KRT14). In humans it is encoded ...
and forms the
intermediate filaments
Intermediate filaments (IFs) are cytoskeletal structural components found in the cells of vertebrates, and many invertebrates. Homologues of the IF protein have been noted in an invertebrate, the cephalochordate ''Branchiostoma''.
Intermedi ...
(IF) that make up the
cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
of
basal epithelial cells
Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...
.
This protein is involved in several diseases including
epidermolysis bullosa simplex
Epidermolysis bullosa simplex (EBS) is a disorder resulting from mutations in the genes encoding keratin 5 or keratin 14.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. . It is one of the major f ...
and breast and lung cancers.
Structure
Keratin 5, like other members of the
keratin
Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. It is the key structural material making up Scale (anatomy), scales, hair, Nail (anatomy), nails, feathers, horn (anatomy), horns, claws, Hoof, hoove ...
family, is an intermediate filament protein. These polypeptides are characterized by a 310 residue central rod domain that consists of four
alpha helix
An alpha helix (or α-helix) is a sequence of amino acids in a protein that are twisted into a coil (a helix).
The alpha helix is the most common structural arrangement in the Protein secondary structure, secondary structure of proteins. It is al ...
segments (helix 1A, 1B, 2A, and 2B) connected by three short linker regions (L1, L1-2, and L2).
The ends of the central rod domain, which are called the helix initiation motif (HIM) and the helix termination motif (HTM), are highly conserved. They are especially important for
helix stabilization, heterodimer formation, and filament formation.
Lying on either side of the central rod are variable, non-helical head and tail regions which protrude from the IF surface and provide specificity to different IF polypeptides.
IF central rods contain
heptad repeat
The heptad repeat is an example of a structural motif that consists of a repeating pattern of seven amino acids:
''a b c d e f g''
H P P H C P C
where H represents hydrophobic residues, C represents, typically, charged residues, and P repre ...
s (repeating seven residue patterns) of
hydrophobic
In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, thu ...
resides that allow two different IF proteins to intertwine into a
coiled-coil
A coiled coil is a structural motif in proteins in which two to seven alpha-helices are coiled together like the strands of a rope. ( Dimers and trimers are the most common types.) They have been found in roughly 5-10% of proteins and have a v ...
formation via
hydrophobic interaction
In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water.
Hydrophobic molecules tend to be nonpolar and, thus, ...
s.
These heterodimers are formed between specific pairs of type I (acidic) and type II (basic) keratin. K5, a type II keratin, pairs with the type I keratin K14.
The coiled-coil dimers undergo
stepwise assembly and combine in an
antiparallel manner, forming end-to-end interactions with other coiled-coils to form large 10 nm intermediate filaments.
Function
Keratin 5 (and K14) are expressed primarily in basal
keratinocyte
Keratinocytes are the primary type of cell found in the epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the basal layer (''stratum basale'') of the skin are sometimes referre ...
s in the
epidermis
The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and Subcutaneous tissue, hypodermis. The epidermal layer provides a barrier to infection from environmental pathogens and regulates the ...
, specifically in the
stratified epithelium lining the skin and digestive tract.
Keratin intermediate filaments make up the cytoskeletal scaffold within epithelial cells, which contributes to the cell architecture and provides the cells with the ability to withstand mechanical, and non-mechanical,
stresses.
K5/K14 keratin pairs are able to undergo extensive bundling due to the non-helical tail of K15 acting as a weak
cross-link
In chemistry and biology, a cross-link is a bond or a short sequence of bonds that links one polymer chain to another. These links may take the form of covalent bonds or ionic bonds and the polymers can be either synthetic polymers or natural ...
er at the intermediate filament surface. This bundling increases the
elasticity, and therefore the mechanical resilience, of the intermediate filaments.
K5/K14 intermediate filaments are anchored to the
desmosomes
A desmosome (; "binding body"), also known as a macula adherens (plural: maculae adherentes) (Latin for ''adhering spot''), is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like ad ...
of basal cells via
desmoplakin
Desmoplakin is a protein in humans that is encoded by the ''DSP'' gene. Desmoplakin is a critical component of desmosome structures in cardiac muscle and epidermal cells, which function to maintain the structural integrity at adjacent cell co ...
and
plakophilin-1, connecting the cells to their neighbours.
At the
hemidesmosome
Hemidesmosomes are very small stud-like structures found in keratinocytes of the epidermis of skin that attach to the extracellular matrix. They are similar in form to desmosomes when visualized by electron microscopy; however, desmosomes attach ...
, plectin and BPAG1 associate with transmembrane proteins α6β4
integrin
Integrins are transmembrane receptors that help cell–cell and cell–extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, o ...
, a type of
cell adhesion molecule
Cell adhesion molecules (CAMs) are a subset of cell surface proteins that are involved in the binding of cells with other cells or with the extracellular matrix (ECM), in a process called cell adhesion. In essence, CAMs help cells stick to each ...
, and
BP180/collagen XVII, linking K5/K14 filaments in the basal cells to the
basal lamina
The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often incorrectly referred to as the basement membrane, though it does constitute a portion of the basement membrane. The b ...
.
Clinical relevance
Epidermolysis bullosa simplex
Epidermolysis bullosa simplex (EBS) is an inherited skin blistering disorder associated with mutations in either K5 or K14.
[.] EBS-causing mutations are primarily
missense mutation
In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn alt ...
s, but a small number of cases arise from
insertions or
deletions. Their mechanism of action is
dominant negative interference, with the mutated keratin proteins interfering with the structure and integrity of the cytoskeleton.
This cytoskeletal disorganization also leads to a loss of anchorage to the hemidesmosomes and desmosomes, causing basal cells to lose their linkage with the basal lamina and each other.
The severity of EBS has been observed to be dependent upon the position of the mutation within the protein, as well as the type of keratin (K5 or K14) that contains the mutation. Mutations that occur at either of the two 10-15 residue “hotspot” regions located on either end of the central rod domain (HIM and HTM) tend to coincide with more severe forms of EBS, whereas mutations at other spots usually result in milder symptoms. Since the “hotspot” regions contain the initiation and termination sequences of the alpha-helical rod, mutations at these spots usually have a larger effect on helix stabilization and heterodimer formation.
Additionally, mutations in K5 tend to result in more severe symptoms than mutations in K14, possibly due to greater
steric interference
Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is generally a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivi ...
.
Cancer
Keratin 5 serves as a
biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
for several different types of cancer, including breast and lung cancers.
It is often tested in conjunction with
keratin 6
Keratin 6A is one of the 27 different type II keratins expressed in humans. Keratin 6A was the first type II keratin sequence determined. Analysis of the sequence of this keratin together with that of the first type I keratin led to the discovery ...
, using
CK5/6 antibodies, which target both keratin forms.
Basal-like breast cancers tend to have poorer outcomes than other types of breast cancer due to a lack of targeted therapies.
These breast cancers do not express
human epidermal growth factor receptor-2 or
receptors
Receptor may refer to:
*Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds ...
for
estrogen
Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
or
progesterone
Progesterone (; P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the ma ...
, making them immune to
Trastuzumab/Herceptin and
hormonal therapies, which are very effective against other breast cancer types. Due to the fact that K5 expression is only seen in basal cells, it serves as an important biomarker for
screening patients with basal-like breast cancers to ensure that they are not receiving ineffective treatment.
Studies on lung cancer have also shown that
squamous cell carcinoma
Squamous-cell carcinoma (SCC), also known as epidermoid carcinoma, comprises a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...
s give rise to tumors with elevated K5 levels, and that they are more likely to arise from
stem cells
In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can change into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type of cell ...
expressing K5 than from those cells without K5 expression.
K5 also serves as a marker of
mesothelioma
Mesothelioma is a type of cancer that develops from the thin layer of tissue that covers many of the internal organs (known as the mesothelium). The area most commonly affected is the lining of the lungs and chest wall. Less commonly the lini ...
, and can be used to distinguish mesothelioma from
pulmonary
The lungs are the primary organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the backbone on either side of the heart. Their function in the respiratory syste ...
adenocarcinoma
Adenocarcinoma (; plural adenocarcinomas or adenocarcinomata ; AC) is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or ...
.
Similarly, it can be used to distinguish
papilloma
A papilloma (plural papillomas or papillomata) ('' papillo-'' + '' -oma'') is a benign epithelial tumor growing exophytically (outwardly projecting) in nipple-like and often finger-like fronds. In this context, papilla refers to the projection cr ...
, which is positive for K5, from
papillary carcinoma, which is K5 negative.
It can also serve as a marker of
basal cell carcinoma
Basal-cell carcinoma (BCC), also known as basal-cell cancer, basalioma, or rodent ulcer, is the most common type of skin cancer. It often appears as a painless, raised area of skin, which may be shiny with Telangiectasia, small blood vessels ru ...
,
transitional cell carcinoma
Transitional cell carcinoma is a type of cancer that arises from the transitional epithelium, a tissue lining the inner surface of these hollow organs. It typically occurs in the urothelium of the urinary system; in that case, it is also called ...
, salivary gland tumors, and
thymoma
A thymoma is a tumor originating from the epithelial cells of the thymus that is considered a rare neoplasm. Thymomas are frequently associated with neuromuscular disorders such as myasthenia gravis; thymoma is found in 20% of patients with myast ...
.
The expression of K5 is linked to the intermediate
phenotype
In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
of cells undergoing the
epithelial-mesenchymal transition (EMT). This process has a large role in tumor progression and
metastasis
Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
since it helps enable tumor cells to travel throughout the body and colonize distant sites. K5 may therefore be useful in the identification of basal cell metastases.
See also
*
Intermediate filament
Intermediate filaments (IFs) are cytoskeleton, cytoskeletal structural components found in the cells of vertebrates, and many invertebrates. Homologues of the IF protein have been noted in an invertebrate, the cephalochordate ''Branchiostoma' ...
*
Keratin
Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. It is the key structural material making up Scale (anatomy), scales, hair, Nail (anatomy), nails, feathers, horn (anatomy), horns, claws, Hoof, hoove ...
*
Keratin 14
Keratin 14 is a member of the type I keratin family of intermediate filament proteins. Keratin 14 was the first type I keratin sequence determined.
Keratin 14 is also known as cytokeratin-14 (CK-14) or keratin-14 (KRT14). In humans it is encoded ...
*
Cytoskeleton
The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is compos ...
*
Epidermolysis bullosa simplex
Epidermolysis bullosa simplex (EBS) is a disorder resulting from mutations in the genes encoding keratin 5 or keratin 14.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. . It is one of the major f ...
*
Basal-like carcinoma
References
Further reading
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External links
GeneReviews/NCBI/UW/NIH entry on Epidermolysis Bullosa Simplex*
{{Cytoskeletal proteins
Keratins