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Human Tyrosinase related protein 1 (TYRP1) is a Zn2+(/Cu2+) metalloenzyme composed of 537 amino acids found in Humans. It is expressed in melanocytes where it plays an important role in pigmentation. TYRP1 is also involved in melanoma and albinism. Therefore, it represents an interesting target for therapy. TYRP1 can also be called : Catalase B or Glycoprotein 75 (gp75).[1]
Synthesis and transportSynthesis and transport
Human Tyrosinase related protein 1 is encoded by the TYRP1 gene, which is located on the chromosome 9p23. The protein is expressed in melanosomes and on the surface of melanocytes and melanoma cells.[1] TYRP1 gene is transcripted in the nucleus of melanocytes. Then, the mRNA will be translated by the ribosomesand the protein will directly be synthesized in the endoplasmic reticulumwhich recognizes the signal sequence located on the protein. Then it will be transported through the Golgi to specific organelles called melanosomes, where pigments are synthesized.[2] During its maturation, TYRP1 is glycosylated in asparagine in positions 96; 104; 181; 304; 350 and 395. The sorting in the trans-Golgi and transport of the TYRP1 protein to melanosome depends on several proteins such as the Phosphoinositide_3-Kinase[2], the membrane associated transporter protein (MATP) [1] and the GAIP interacting protein (GIPC).[3] The final TYRP1 protein is 537 amino-acids long. TYRP1 is transported to the membrane by the biogenesis of lysosome-related organelles complex 1 (BLOC-1). The amino-terminal domain will be oriented in the lumen of the melanosome, and the carboxy terminal domain in the cytoplasm of the melanocyte.[3] TYRP1 is only found in the membrane of mature stage III and IV melanosomes.[1]
FunctionFunction
Role in melanocytesRole in melanocytes
First, TYRP1 has a role in melanin biosynthesis. Indeed, this enzyme has a catalytic function in the melanin biosynthetic pathway. In mice, when a Cu2+ cation is bound, the protein catalyzes the oxidation of 5,6-dihydroxyindole-2-carboxylic acid (DHICA) into indole-5,6-quinone-2-carboxylic acid. This protein is also able to catalyze the oxidation of 5,6-dihydroxyindole (DHI) into indole-5,6-quinone. Both products will allow to obtain eu-melanin, while pheo-melanin is obtained thanks to TYRP2 activity.[4] The activity of the TYRP1 enzyme increases when the serine residues in position 505 and 509 are phosphorylated.[3] However, this mechanism does not happened in Humans because Human TYRP1 does not have the DHCIA activity. This can be explained by the fact that the nature of ions in the active site is different. Indeed, two Zn2+ ions bind the active site of the TYRP1 enzyme instead of two Cu2+, which are responsible for a different activity.[5] In fact, the incorporation of Cu2+ instead of Zn2+ in human TYRP1 active site, gives to the enzyme the DHICA activity, but no experiment has shown that Cu2+ can replace Zn2+ in vivo conditions.[6] To conclude, the exact role of TYRP1 in pigmentation remains still unclear. Moreover, no gene polymorphism has been observed among caucasian populations, despite the variation of hair and skin colors.[7] In addition, the mouse homolog of the TYRP1 is involved in melanocytes differenciation too. Therefore, it could be used as a differentiation marker.[8] In humans beings, the exact role of TYRP1 in differentiation of melanocyte is unclear. However, it is supposed that the protein is involved in the mechanism, as it is involved in pigmentation.
Role in melanomaRole in melanoma
TYRP1 also has a role in the progression of melanoma. In fact, as TYRP1 is involved in the proliferation and differentiation of melanocytes, a mutation of the protein is associated with a higher risk for melanoma [1]. Therefore, the level of expression of TYRP1 mRNA is a prognostic marker.[9]
Structural highlightsStructural highlights
Main domains and latticesMain domains and lattices
The 3D-structure at the top of the page represents the biological unit, it is the working part of the enzyme in in-vivo conditions but there is also a 3D-structure for the of TYRP1. The 3D-structure of the biological unit represents only the amino acids between 25 and 470 of the sequence.
TYRP1 is a globular monomeric protein. It is composed of several domains: a short peptide signal (0-25) on the N-terminal side followed by a large intra-melanosomal domain. This intra-melanosomal domain contains a cystein-rich domain and a catalytic tyrosinase-like subdomain with two ion-binding sites.[6] The next part of the sequence (not represented on the 3D-structure) is composed of a transmembrane α-helix (478-502) followed by a short cytoplasmic sequence on the C-terminal chain(503-537).[10]
- The cystein-rich subdomain (25-126)
The has an epidermal growth factor‐like fold formed by [5] . This previous domain strongly interacts with the tyrosinase-like subdomain by the lastloop of the cystein-rich domain preceding the N-terminal domain. This domain is stabilized by and is located at the opposite of the active site. The role of the cystein-rich domain is still unknown, it is only found in mammalians. It is said that the cystein-rich domain might help the formation of a complex between TYR and TYRP2.[6][5]
- The tyrosinase-like subdomain (127-477)
The is composed of four helix bundle connected by long loops and stabilized by . This domain interacts with cystein-rich domain located on the same side of tyrosinase-like subdomain.[5]
- Other information
TYRP1 has which are essential for the protein maturation. On our 3D structure all these sites are glycosylated.
The active siteThe active site
- Structure
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is located in the tyrosinase-like subdomain. It is delimited by four helices and contains the binuclear metal-binding site. It looks like type-3 binuclear copper-binding site of Tyrosinases. Both ions are bound with planar trigonal geometry and the distance between them is : 3,5 ± 0,1 Ā. A molecule of water located at the same distance (2,1 ± 0,1 Ā) from the two ions can make a bridge between them. Mutations on amino acids of the active site do not significantly affect TYRP1 activity.[5]
- Ligand interactions
The crystal structure of TYRP1 shows that TYRP1 can bind tyrosine, mimosine (DOPA equivalent), kojic acid, tropolone. DOPA and tyrosine can interact with the active site by their aromatic hydroxy or keto groups through hydrogen bounds with water molecule between the ions. Aromatic stacking interactions with H381 and hydrogen bonds between carboxylate group, Arg374 and Ser394 represent between these substrates and amino acids close to the active site. Tropolone has direct interactions with one of the Zn2+ ion because of its metal-chelating property. The interactions between tropolone and Zn2+ show that the binuclear site is flexible. The ring hydroxy and keto groups of kojic acid bind the Zinc ion away from 3Ā. All these non specific interactions may confirm that TYRP1 can have several roles.[5] The bonds between the protein and its inhibitors are not affected by change in hydrogen bounds. It can be interesting to study this property to design better inhibitors. The future discovery of TRP1 role in melanin synthesis may be a breakthrough for the cosmetic industry.[10]
Comparison between enzymes of the Tyrosinase familyComparison between enzymes of the Tyrosinase family
In mammals, three enzymes of Tyrosinase family may be involved in the biosynthesis of melanin. Tyrosinase (TYR) reacts two times in the mechanism whereas Tyrosinase Related Protein 1 and 2 (TYRP1 and TYRP2) probably catalyze only one reaction in this biosynthesis. TYR is an oxydoreductase,TYRP2 seems to act as a tautomerase and the exact role in melanin synthesis of human TYRP1 is still under debate. In fact in mice, TYRP1 can especially catalyze the reaction of DHICA in eumelanin but human TYR can also do the same.[10] No human cristal structure is available for TYR, so thanks to cristal structure of TYRP1, it is possible to deduce a good model of TYR.
SimilaritiesSimilarities
All three melanogenic enzymes are metal-containing glycoproteins with an amino acid correspondence of 40% and a sequence analogy of 70%. A multiple sequence alignment demonstrates four conserved regions for Tyrosinase related protein 1, Tyrosinase (Tyr) and Tyrosinase related protein 2 (TYRP2).[10] Initially, a signal peptide exists at the C-terminus and possesses 24 residues. Secondly, the enzymes consist of an intramelanosomal or luminal domain with 453 residues divided into two subdomains. The cysteine-rich subdomain (102 residues) shows a fold like the human epidermal growth factor (EGF) whereas the tyrosinase-like subdomain (351 residues) exhibits a fold similar to the bacterial tyrosinase of Bacillus megaterium (TyrBm). Thirdly, the glycoproteins contain a single transmembrane α-helix whereat 24 residues are associated. Ultimately, the N-terminus is composed of a flexible cytoplasmic domain with 36 residues.[5]
According to crystal knowledges, it is said that TYRP1 and TYR can bind the same substrates and even if the composition of the active site is different, it does not affect the binding modes of these compounds.[5] The three enzymes have several sites of N-glycosylation which are necessary for their maturation, two of these sites are shared by the three enzymes. TYRP1 and 2 have both six sites and among them, four are exactly the same.[6]
DifferencesDifferences
The main difference between these three enzymes is the nature of metal ions they bind on the active site. TYRP1 and TYRP2 bind two zinc ions whereas TYR binds two copper ions. Therefore these enzymes catalyze different reactions: TYR catalyzes the conversion of tyrosine into L-DOPA and then in Dopaquinone,TYRP2 isomerizes dopachrome to DHICA. Moreover, the active site of TYRP2 contains two molecules of water and a substrate interacting with both Zn2+ during reactions, whereas TYRP1 active site contains only one molecule of water and a substrate which are interacting with only one Zn2+ ion(ZnA). However, no 3D-structure of TYRP2 is currently available so the exact coordination of metal ions in the active site stays unclear.[6] Besides, TYRP1 has the longuest sequence of the three proteins (TYR : 529, TYRP2 : 519, TYRP1 : 537) and contrary to TYRP1 and TYRP2, TYR contains six sites of N-glycosylation.[6]
Related diseasesRelated diseases
Oculocutaneous albinism 3Oculocutaneous albinism 3
Oculocutaneous albinism 3 (OCA3) is a mild form of congenital disorders in the biosynthesis of melanin whereat generally four further types (OCA1A, OCA1B, OCA2 and OCA4) are distinguished.[11] The disease can be caused by a number of mutations in the TYRP1 gene on chromosome nine (9p23) which are autosomal recessive inherited and mostly influence the stability of the expressed protein. Eight OCA3-related single-residue alterations have so far been found.
- C30R is part of the disulfide bond C30-C41 which attaches the α-helix 1 to the core of the cysteine-rich subdomain.
- R93C is close to the disulfide bonds C30-C41, C42-C65, C56-C99 and C101-C110 and interferes with the cluster formation or correct folding.
- H215Y is a ligand of the first zinc ion ZnA in the active site and reduces the binding affinity and catalytic activity.
- T253M is located on the surface loop of the tyrosinase-like subdomain and leads to local unfolding or regional aggregation.
- C290Y is part of the disulfide bond C290-C303 which stabilizes the loop 290-303 of the tyrosinase-like subdomain.
- R356Q is located in an extensive hydrogen bonding network of the tyrosinase-like subdomain.
- M452V forms the interface between the cysteine-rich and tyrosinase-like subdomain.
- P513R is located in the flexible cytoplasmic domain and interferes with the translocation of the enzyme to the melanosomal membrane.
The phenotypical expression of the missense mutations T253M and M452V are yet to be confirmed whereas the other point mutations are pathological.[5] Affected individuals have red coloured hair and rufous skin complexion. However, since OCA3 permits some melanin accumulation over time, the hypopigmentation does not suffice to alter the eye development. Thus, feature bearers may possess a green iris but no significant visual anomalies.[11]
MelanomaMelanoma
Melanoma is a malignant proliferation of the pigment-forming cells which spreads metastasis through the lymph system and blood stream. Abnormalities primarily occur in the skin (cutaneous melanoma) but may also be found in the vascular layer of the eye (uveal melanoma), the central nervous system (leptomeningeal melanoma) or the mucous membranes of mouth, nose, intestines, anus and vagina (mucosal melanoma).
In order to describe the extent of disease progression, the staging system by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) is applied whereat the key features are tumor size, lymph node involvement and metastasis spread (TLM).[12]
Despite the significant histopathological criteria, the clinical behavior of melanoma is, due to various biological subtypes, often unpredictable. However, microarray analysis and molecular profiling of skin metastasis indicate that the TYRPI mRNA expression level is a prognostic marker for Melanoma. A high transcript amount correlates with short patient survival whereat the distant metastasis-free survival (DMFS), overall survival (OS) and Breslow thickness are affected.[9]
ReferencesReferences
[1] Ghanem, G., & Fabrice, J. (2011). Tyrosinase related protein 1 (TYRP1/gp75) in human cutaneous melanoma. Molecular oncology, 5(2), 150–155. doi:10.1016/j.molonc.2011.01.006 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5528278/
[2] Chen H., Salopek T.G., Jimbow K., 2001. The role of phosphoinositide 3-kinase in the sorting and transport of newly synthesized tyrosinase related protein-1 (TRP1). J. Investig. Dermatol. Symp. Proc.. 6, (1) 105–114 PMID: 21324755
https://www.jidsponline.org/article/S0022-202X(15)52884-4/fulltext
[3] Liu T.F., Kandala G., Setaluri V., 2001. PDZ-domain protein GIPC interacts with the cytoplasmic tail of melanosomal membrane protein gp75 (tyrosinase related protein-1). J. Biol. Chem.. 276, 35768–35777 PMID: 11441007 doi: 10.1074/jbc.M103585200
http://www.jbc.org/content/276/38/35768.full
[4] Kobayashi, T., Urabe, K., Winder, A., Jiménez-Cervantes, C., Imokawa, G., Brewington, T., … Hearing, V. J. (1994). Tyrosinase related protein 1 (TRP1) functions as a DHICA oxidase in melanin biosynthesis. The EMBO journal, 13(24), 5818–5825.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC395555/
[5] Lai, X., Wichers, H. J., Soler-Lopez, M., & Dijkstra, B. W. (2017). Structure of Human Tyrosinase Related Protein 1 Reveals a Binuclear Zinc Active Site Important for Melanogenesis. Angewandte Chemie (International ed. in English), 56(33), 9812–9815. doi:10.1002/anie.201704616
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601231/
[6] Xuelei Lai, Harry J. Wichers, Montserrat Soler‐Lopez, Bauke W. Dijkstra. Structure and Function of Human Tyrosinase and Tyrosinase‐Related Proteins. 2018 Jan 2 Epub 2017 Nov 28 PMID: 29052256 https://www.ncbi.nlm.nih.gov/pubmed/29052256 doi: 10.1002/chem.201704410
https://onlinelibrary.wiley.com/doi/abs/10.1002/chem.201704410
[7] Box N.F., Wyeth J.R., Mayne C.J., O'Gorman L.E., Martin N.G., Sturm R.A., 1998. Complete sequence and polymorphism study of the human TYRP1 gene encoding tyrosinase-related protein. Mamm. Genome. 9, 50–53 PMID:9434945 doi:10.1007/s003359900678
https://link.springer.com/article/10.1007/s003359900678#citeas
[8] Vijayasaradhi, S., Bouchard, B., & Houghton, A. N. (1990). The melanoma antigen gp75 is the human homologue of the mouse b (brown) locus gene product. The Journal of experimental medicine, 171(4), 1375–1380. doi:10.1084/jem.171.4.1375
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2187848/
[9] Journe, F., Id Boufker, H., Van Kempen, L., Galibert, M. D., Wiedig, M., Salès, F., … Ghanem, G. (2011). TYRP1 mRNA expression in melanoma metastases correlates with clinical outcome. British journal of cancer, 105(11), 1726–1732. doi:10.1038/bjc.2011.451
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3242608/
[10] Decker H., Tuczek F. The Recent Crystal Structure of Human Tyrosinase Related Protein 1 (HsTYRP1) Solves an Old Problem and Poses a New One. 2017 Nov 13. Epub 2017 Oct 9 PMID: 28990327 https://www.ncbi.nlm.nih.gov/pubmed/28990327 doi: 10.1002/anie.201708214
https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.201708214
[11] Grønskov, K., Ek, J., & Brondum-Nielsen, K. (2007). Oculocutaneous albinism. Orphanet journal of rare diseases, 2, 43. doi:10.1186/1750-1172-2-43
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211462/
[12] In Stewart, B. W., & In Wild, C. P. (2014). World cancer report 2014. Chapter 5.14 Skin cancer, pp. 495-502
http://publications.iarc.fr/Non-Series-Publications/World-Cancer-Reports/World-Cancer-Report-2014
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