Sandbox TYRP1

Tyrosinase related protein 1 (5M8L)Tyrosinase related protein 1 (5M8L)

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Human Tyrosinase related protein 1 (TYRP1) is a Cu2+/Zn2+ metalloenzyme 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).

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. TYRP1 protein is synthesized in the nucleus of melanosomes thanks to a signaling sequence. Then, it will be translated by the ribosomesand the protein will be directly transported in the endoplasmic reticulum. Then it will be transported through the Golgi to a specific organelles called melanosomes, where pigments are synthesized. 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 is dependant of several proteins such as the Phosphoinositide_3-Kinase, the membrane associated transporter protein (MATP) and the GAIP interacting protein (GIPC). 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) (wikipedia). The amino-terminal domain will be oriented in the lumen of the melanosome, and the carboxy terminal domain in the cytoplasm of the melanocyte. TYRP1 is found only in the membrane of mature stage III and IV melanosomes.

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 mouse, 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 obtain thanks to TYRP2 activity. The activity of the TYRP1 enzyme increase when the serine residues in position 505 and 509 are phosphorylated . However, this mechanism does not happens in Humans because Human TYRP1 does not have the DHCIA activity. This can be explain by the fact that the nature of ions in the active site is different. Indeed, a Zn2+ ion bounds the active site of the TYRP1 enzyme instead of a Cu2+, which is responsible for a different activity. To conclude, the exact role of TYRP1 in pigmentation remains still unclear. Moreover, no gene polymorphism has been observed among caucasian population, despite the variation of hair and skin colors. In addition, the mouse homolog of the TYRP1 is involved in melanocytes differenciation too. Therefore, it could be used as a differentiation marker. In humans, 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 have a role in 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. Therefore, the level of expression of TYRP1 mRNA is prognostic marker.

Structural highlightsStructural highlights

Main domains and latticesMain domains and lattices

TYRP1 is a globular monomeric protein. It is composed of several domains: a short peptide signal on the N-terminal side followed by a large intra-melanosomal domain. This intra-melanosomal domain contain a rich-cysteine domain and a catalytic tyrosinase-like subdomain with two ion-binding sites. The next part of the sequence is composed of a transmembrane alpha helix followed by a short cytoplasmic sequence on the C-terminal chain.

The cystein-rich domain and the tyrosinase-like subdomain stongly interact together by the last loop of the cystein-rich domain preceding the N-terminal domain. The role of the cystein-rich domain is still unknown, it is only found in mammalians but 3D-structure highlights two pairs of short antiparallel beta-strands which create loops. This domain is stabilize by five disulfide bounds and is located at the opposite of the active site. It is sad that the cystein_rich domain might help to the formation of a complexe between TYR and TYRP2.

The active siteThe active site

The active site is delimited by four helice and contain the binuclearmetal binding site. (image à faire)

Comparison between enzymes of Tyrosinase familyComparison between enzymes of Tyrosinase family

In mammals, three enzymes of Tyrosinase family may be involved in 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 mices, TYRP1 can especially catalyze the reaction of DHICA in eumelanin but human TYR can also do the same. It is said that TYRP1 can play a significant role in proliferation of melanosomes.

(Image à faire reaction chimique)

Similarities:Similarities:

All three melanogenic enzymes are metal-containing glycoproteins and have a single transmembrane alpha-helix. 40% of their amino acid sequence is exactly the same and 70% of their sequences are analogous In fact, multiple human sequence aligment show that Tyrosinase (TYR), TYRP1 and 2 have following similar domains. First, a short peptide signal on the N-terminal side followed by a large intra-melanosomal domain. This intra-melanosomal domain contain a rich-cysteine domain and a catalytic tyrosinase-like subdomain with two ion-binding sites. After that there is a transmembrane alpha helix followed by a short cytoplasmic sequence on the C-terminal chain.

(image à faire)

These three proteins share similar active sites. Metal ions interact with three histidines.

Differences:Differences:

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

Interet des ions !!! The binds 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 cosmetic industry.

ReferencesReferences

Ghanem, G., and Fabrice, J. Tyrosinase related protein 1 (TYRP1/gp75) in human cutaneous melanoma. Molecular Oncology, 2011,5(2): 150–155. PMID: 21324755

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

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