1. Discovery

2. Gene location

3. Protein localisation

4. Function

5. Structure

6. Post-translational modifications

7. Interactions

8. Clinical significance

9. References

10. Further reading

Discovery

In 1903 the name “trichohyalin” was assigned to the granules of the inner root sheath (IRS) of hair follicles discovered by H. Voerner.^[2] In 1986 the name was reassigned to a protein isolated from sheep wool follicles.^[3]

Gene location

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 ([https://www.ncbi.nlm.nih.gov/genome/gdv/browser/?context=gene&acc=7062 map]).^[4] 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.^[5] Gene orthologs were identified in most mammals including mice, chickens, rats, pigs, sheep, horses and other species.^[6]

Protein localisation

Trichohyalin is highly expressed in the inner root sheath cells of the hair follicle and medulla.^[7] It was also detected in the granular layer and stratum corneum of normal epidermis,^[8] newborn human foreskin epidermis, the hard palate, in the nail matrix, the filiform papillae of dorsal tongue epithelium and in rodent forestomack.^[9]

Function

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.^[7]

Overall, trichohyalin confers mechanical strength to the hair follicle inner root sheath and to other toughened epithelial tissues.^[7]

Structure

Trichohyalin belongs to the S100-fused protein family. It is a monomer, containing 1943 amino acids,^[10] and has elongated (>200 nm) single-stranded alpha-helical conformation based on its unusually high content of charged residues.^[11]

Molecular mass of the human trichohyalin is 253925 Da.^[10]

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.^[10][11]

Post-translational modifications

• Peptidylarginine deiminases (PAD) catalyse the deimination of arginine residues to citrullines.^[12]
• 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.^[12]

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.^[7]

The protein can also form cross-links to all other CE proteins including involucrin, envoplakin, keratin, repetin, desmoplakin, SPR1, SPR2, and LEP.^[7]

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.^[7]

Clinical significance

Trichohyalin is associated with uncombable hair syndrome,^[13] human alopecia areata ^[14] and also may be linked to curly hair phenotype in Europeans.^[15]

A weak expression of the protein was discovered in the horny layer of psoriasis, ichthyosis, keratosis pilaris, porokeratosis, chronic dermatitis and callus.^[16] 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).^[16]

References

Further reading

• {{cite journal | vauthors = Eriksson N, Macpherson JM, Tung JY, Hon LS, Naughton B, Saxonov S, Avey L, Wojcicki A, Pe'er I, Mountain J | title = Web-based, participant-driven studies yield novel genetic associations for common traits | journal = PLoS Genetics | volume = 6 | issue = 6 | pages = e1000993 | date = June 2010 | pmid = 20585627 | pmc = 2891811 | doi = 10.1371/journal.pgen.1000993 | editor1-last = Gibson | editor1-first = Greg }}
• {{cite journal | vauthors = Yamamoto S, Hirai K, Hasegawa-Oka Y, Hirai Y | title = Molecular elements of the regulatory control of keratin filament modulator AHF/trichohyalin in the hair follicle | journal = Experimental Dermatology | volume = 18 | issue = 2 | pages = 152–9 | date = February 2009 | pmid = 18643848 | pmc = | doi = 10.1111/j.1600-0625.2008.00777.x }}
• {{cite journal | vauthors = Lee SC, Wang M, McBride OW, O'Keefe EJ, Kim IG, Steinert PM | title = Human trichohyalin gene is clustered with the genes for other epidermal structural proteins and calcium-binding proteins at chromosomal locus 1q21 | journal = The Journal of Investigative Dermatology | volume = 100 | issue = 1 | pages = 65–8 | date = January 1993 | pmid = 8423399 | doi = 10.1111/1523-1747.ep12354504 }}
• {{cite journal | vauthors = Steinert PM, Parry DA, Marekov LN | title = Trichohyalin mechanically strengthens the hair follicle: multiple cross-bridging roles in the inner root shealth | journal = The Journal of Biological Chemistry | volume = 278 | issue = 42 | pages = 41409–19 | date = October 2003 | pmid = 12853460 | pmc = | doi = 10.1074/jbc.M302037200 }}
• {{cite journal | vauthors = O'Keefe EJ, Hamilton EH, Lee SC, Steinert P | title = Trichohyalin: a structural protein of hair, tongue, nail, and epidermis | journal = The Journal of Investigative Dermatology | volume = 101 | issue = 1 Suppl | pages = 65S-71S | date = July 1993 | pmid = 7686953 | doi = 10.1111/1523-1747.ep12362866 }}
• {{cite journal | vauthors = Fietz MJ, Rogers GE, Eyre HJ, Baker E, Callen DF, Sutherland GR | title = Mapping of the trichohyalin gene: co-localization with the profilaggrin, involucrin, and loricrin genes | journal = The Journal of Investigative Dermatology | volume = 99 | issue = 5 | pages = 542–4 | date = November 1992 | pmid = 1431214 | doi = 10.1111/1523-1747.ep12667301 }}
• {{cite journal | vauthors = Medland SE, Nyholt DR, Painter JN, McEvoy BP, McRae AF, Zhu G, Gordon SD, Ferreira MA, Wright MJ, Henders AK, Campbell MJ, Duffy DL, Hansell NK, Macgregor S, Slutske WS, Heath AC, Montgomery GW, Martin NG | title = Common variants in the trichohyalin gene are associated with straight hair in Europeans | journal = American Journal of Human Genetics | volume = 85 | issue = 5 | pages = 750–5 | date = November 2009 | pmid = 19896111 | pmc = 2775823 | doi = 10.1016/j.ajhg.2009.10.009 }}
• {{cite journal | vauthors = Leung MC, Sutton CW, Fenton DA, Tobin DJ | title = Trichohyalin is a potential major autoantigen in human alopecia areata | journal = Journal of Proteome Research | volume = 9 | issue = 10 | pages = 5153–63 | date = October 2010 | pmid = 20722389 | pmc = | doi = 10.1021/pr100422u }}
• {{cite journal | vauthors = Lee SC, Kim IG, Marekov LN, O'Keefe EJ, Parry DA, Steinert PM | title = The structure of human trichohyalin. Potential multiple roles as a functional EF-hand-like calcium-binding protein, a cornified cell envelope precursor, and an intermediate filament-associated (cross-linking) protein | journal = The Journal of Biological Chemistry | volume = 268 | issue = 16 | pages = 12164–76 | date = June 1993 | pmid = 7685034 }}

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