Trichohyalin

In 1903 the name trichohyalin was assigned to the granules of the inner root sheath (IRS) of hair follicles discovered by Hans Vörner.[6] In 1986 the name was reassigned to a protein isolated from sheep wool follicles.[7]

The human TCHH is located on the long (q) arm of chromosome 1 at region 2 band 1 sub-band 3 (1q21.3), from base pair 152,105,403 to base pair 152,116,368 (map).[8] This region in chromosome 1q21 is known as the epidermal differentiation complex, since it harbors over fifty other genes involved in keratinocyte differentiation.

Gene coding sequence contains 5829 nucleotides.[9] Gene orthologs were identified in most mammals including mice, chickens, rats, pigs, sheep, horses and other species.[10]

Trichohyalin is highly expressed in the inner root sheath cells of the hair follicle and medulla.[11] It was also detected in the granular layer and stratum corneum of normal epidermis,[12] newborn human foreskin epidermis, the hard palate, in the nail matrix, the filiform papillae of dorsal tongue epithelium and in rodent forestomach.[13]

The protein forms frequent links between the heads and tails of the keratin 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.[11]

Overall, trichohyalin confers mechanical strength to the hair follicle inner root sheath and to other toughened epithelial tissues.[11]

Trichohyalin belongs to the S100-fused protein family. It is a monomer, containing 1943 amino acids,[14] and has elongated (>200 nm) single-stranded alpha-helical conformation based on its unusually high content of charged residues.[15]

Molecular mass of the human trichohyalin is 253925 Da.[14]

The protein includes nine domains. Domain 1 contains two EF-hand calcium-binding domains.  Domains 2-4, 6, and 8 are almost entirely alpha-helical, configured as a series of peptide 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.[14][15]

• Peptidylarginine deiminases (PAD) catalyse the deimination of arginine residues to citrullines.[16]
• Cross-linking by transglutaminase (TGase) enzymes results in the formation of an isopeptide bond between peptide-bound glutamine and lysine residues and provide insolubility and the rigid structure to trichohyalin.[16]

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.[11]

The protein can also form cross-links to all other CE proteins including involucrin, envoplakin, keratin, repetin, desmoplakin, SPR1, SPR2, and LEP.[11]

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.[11]

Trichohyalin is associated with uncombable hair syndrome,[17] human alopecia areata[18] and also may be linked to curly hair phenotype in Europeans.[19]

A weak expression of the protein was discovered in the horny layer of psoriasis, ichthyosis, keratosis pilaris, porokeratosis, chronic dermatitis and callus.[20] The same level of trichohyalin expression was found in epidermal tumours (seborrheic keratosis, actinic keratosis, Bowen's disease, well-differentiated squamous cell carcinoma) and follicular tumours (trichoepithelioma, keratotic basal cell epithelioma, proliferating trichilemmal tumour, trichilemmoma, pilomatricoma and keratoacanthoma).[20]