Trichohyalin is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in

mammal Mammals () are a group of vertebrate animals constituting the class Mammalia (), characterized by the presence of mammary glands which in females produce milk for feeding (nursing) their young, a neocortex (a region of the brain), fur or ...

s is encoded by the ''TCHH''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

Discovery

In 1903 the name ''trichohyalin'' was assigned to the granules of the

inner root sheath The inner root sheath or internal root sheath of the hair follicle is located between the outer root sheath and the hair shaft.James, William; Berger, Timothy; Elston, Dirk (2005) ''Andrews' Diseases of the Skin: Clinical Dermatology'' (10th ed.). S ...

(IRS) of

hair follicle The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction between h ...

s discovered by Hans Vörner. In 1986 the name was reassigned to a protein isolated from sheep wool follicles.

Gene location

The human TCHH is located on the long (q) arm of

chromosome A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

1 at region 2 band 1 sub-band 3 (1q21.3), from base pair 152,105,403 to base pair 152,116,368
map
. This region in chromosome 1q21 is known as the

epidermal differentiation complex The epidermal differentiation complex (EDC) is a gene complex comprising over fifty genes encoding proteins involved in the terminal differentiation and cornification of keratinocytes, the primary cell type of the epidermis. In humans, the complex ...

, since it harbors over fifty other genes involved in keratinocyte differentiation. Gene

coding sequence The coding region of a gene, also known as the coding sequence (CDS), is the portion of a gene's DNA or RNA that codes for protein. Studying the length, composition, regulation, splicing, structures, and functions of coding regions compared to no ...

contains 5829 nucleotides. Gene orthologs were identified in most mammals including mice, chickens, rats, pigs, sheep, horses and other species.

Protein localisation

Trichohyalin is highly expressed in the inner root sheath cells of the hair follicle and medulla. It was also detected in the granular layer and

stratum corneum The stratum corneum (Latin for 'horny layer') is the outermost layer of the epidermis. The human stratum corneum comprises several levels of flattened corneocytes that are divided into two layers: the ''stratum disjunctum'' and ''stratum compact ...

of normal epidermis, newborn human foreskin

epidermis The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water rele ...

, the

hard palate The hard palate is a thin horizontal bony plate made up of two bones of the facial skeleton, located in the roof of the mouth. The bones are the palatine process of the maxilla and the horizontal plate of palatine bone. The hard palate spans ...

, in the nail matrix, the filiform papillae of dorsal tongue epithelium and in rodent forestomach.

Function

The protein forms frequent links between the heads and tails of the

keratin Keratin () is one of a family of structural fibrous proteins also known as ''scleroproteins''. Alpha-keratin (α-keratin) is a type of keratin found in vertebrates. It is the key structural material making up scales, hair, nails, feathers, ho ...

chains and, thus, participates in keratin intermediate filaments (KIF) inter-filamentous cross-linking. It also carries a function of a major reinforcement cross-bridging protein for the cell envelope (CE) barrier structure of the IRS and participates in coordination of CE structure. Overall, trichohyalin confers mechanical strength to the hair follicle inner root sheath and to other toughened

epithelial tissue Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...

Structure

Trichohyalin belongs to the S100-fused protein family. It is a monomer, containing 1943

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

s, and has elongated (>200 nm) single-stranded

alpha-helical The alpha helix (α-helix) is a common motif in the secondary structure of proteins and is a right hand-helix conformation in which every backbone N−H group hydrogen bonds to the backbone C=O group of the amino acid located four residues e ...

conformation based on its unusually high content of charged residues. Molecular mass of the human trichohyalin is 253925 Da. The protein includes nine domains. Domain 1 contains two

EF-hand The EF hand is a helix–loop–helix structural domain or ''motif'' found in a large family of calcium-binding proteins. The EF-hand motif contains a helix–loop–helix topology, much like the spread thumb and forefinger of the human hand, in ...

calcium-binding domains. Domains 2-4, 6, and 8 are almost entirely alpha-helical, configured as a series of

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A ...

repeats of varying regularity, and are thought to form a single-stranded alpha-helical rod stabilised by ionic interactions. Domain 6 is the most regular and may bind KIF directly by ionic interactions. Domains 5 and 7 are less well organised and may induce folds in the molecule. Domain 9 contains the C-terminus, conserved among different species.

Post-translational modifications

* Peptidylarginine deiminases (PAD) catalyse the deimination of arginine residues to

citrulline The organic compound citrulline is an α-amino acid. Its name is derived from ''citrullus'', the Latin word for watermelon. Although named and described by gastroenterologists since the late 19th century, it was first isolated from watermelon in 1 ...

s. * Cross-linking by

transglutaminase Transglutaminases are enzymes that in nature primarily catalyze the formation of an isopeptide bond between γ-carboxamide groups ( -(C=O)NH2 ) of glutamine residue side chains and the ε-amino groups ( -NH2 ) of lysine residue side cha ...

(TGase) enzymes results in the formation of an isopeptide bond between peptide-bound glutamine and

lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...

residues and provide insolubility and the rigid structure to trichohyalin.

Interactions

TCHH protein is extensively cross-linked to itself in the IRS tissue as well as to keratin intermediate filaments (KIF). All TCHH-keratin links involved only domain 6 or 8 sequences. The protein can also form cross-links to all other CE proteins including involucrin,

envoplakin Envoplakin is a protein that in humans is encoded by the ''EVPL'' gene. Interactions Envoplakin has been shown to interact Advocates for Informed Choice, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c) ...

, keratin,

repetin Repetin is an extracellular matrix protein expressed in the epidermis. In humans it is encoded by the ''RPTN'' gene. Repetin is part of the S100 fused-type protein family and contains an EF hand structural domain. It functions in the cornified cel ...

, desmoplakin, SPR1, SPR2, and LEP. TCHH-TCHH and TCHH-CE protein links are distributed among domains 2–5, but are uncommon in domains 6 and 8. Most intra-THH cross-links occurred in the least organised domain 5 region at a 3.5-fold higher frequency.

Clinical significance

Trichohyalin is associated with uncombable hair syndrome, human alopecia areata and also may be linked to

curly hair Curly is a surname, given name, nickname or stage name. It may refer to: First name, nickname or stage name * Crazy Horse (1840–1877), Oglala Sioux war chief nicknamed "Curly" * Curly (scout), nickname of Ashishishe (c. 1856–1923), Crow Ind ...

phenotype in Europeans. A weak expression of the protein was discovered in the horny layer of

psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to complete ...

, ichthyosis, keratosis pilaris,

porokeratosis Porokeratosis is a specific disorder of keratinization that is characterized histologically by the presence of a cornoid lamella, a thin column of closely stacked, parakeratotic cells extending through the stratum corneum with a thin or absent gra ...

, chronic dermatitis and callus. The same level of trichohyalin expression was found in epidermal tumours (

seborrheic keratosis A seborrheic keratosis is a non-cancerous (benign) skin tumour that originates from cells, namely keratinocytes, in the outer layer of the skin called the epidermis. Like liver spots, seborrheic keratoses are seen more often as people age. The tum ...

actinic keratosis Actinic keratosis (AK), sometimes called solar keratosis or senile keratosis, is a pre-cancerous area of thick, scaly, or crusty skin.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. . Actinic k ...

, Bowen's disease, well-differentiated

squamous cell carcinoma Squamous-cell carcinomas (SCCs), also known as epidermoid carcinomas, comprise 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 ...

) and follicular tumours (

trichoepithelioma Trichoepithelioma is a neoplasm of the adnexa of the skin. Its appearance is similar to basal cell carcinoma. One form has been mapped to chromosome 9p21. Types Trichoepitheliomas may be divided into the following types: :* Multiple familial ...

, keratotic basal cell epithelioma, proliferating

trichilemmal The inner or epidermic coat of the hair follicle is closely adherent to the root of the hair, and consists of two strata named respectively the outer and inner root sheaths. Outer root sheath The outer root sheath corresponds with the stratum m ...

tumour,

trichilemmoma Trichilemmoma (also known as "tricholemmoma"Busam Klaus J., ''Dermatopathology'' s.386; 2010 Saunders ) is a benign cutaneous neoplasm A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or pr ...

pilomatricoma Pilomatricoma, is a benign skin tumor derived from the hair matrix. These neoplasms are relatively uncommon and typically occur on the scalp, face, and upper extremities. Clinically, pilomatricomas present as a subcutaneous nodule or cyst with un ...

and keratoacanthoma).