Sandbox TYRP1: Difference between revisions

Human Tyrosinase related protein 1 is encoded by the TYRP1 gene, which is located on the chromosome 9p23.  The protein is expressed in [https://en.wikipedia.org/wiki/Melanosome melanosomes] and on the surface of melanocytes and melanoma cells <ref name="ghanem"/>. TYRP1 protein is synthesized in the nucleus of melanosomes thanks to a signaling sequence. Then, it will be translated by the [https://en.wikipedia.org/wiki/Ribosome ribosomes]and the protein will be directly transported in the [https://en.wikipedia.org/wiki/Endoplasmic_reticulum endoplasmic reticulum]. Then it will be transported through the [https://en.wikipedia.org/wiki/Golgi_apparatus Golgi] to a specific organelles called melanosomes, where pigments are synthesized <ref name="chen"/>. 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 [https://fr.wikipedia.org/wiki/Phosphoinositide_3-kinase Phosphoinositide_3-Kinase]<ref name="chen"/>, the [https://www.uniprot.org/uniprot/Q9UMX9 membrane associated transporter protein] (MATP) <ref name="ghanem"/> and the [https://www.uniprot.org/uniprot/Q8TF64 GAIP interacting protein] (GIPC)<ref name= "liu"/>. The final TYRP1 protein is 537 amino-acids long. TYRP1 is transported to the membrane by the biogenesis of [https://en.wikipedia.org/wiki/Biogenesis_of_lysosome-related_organelles_complex_1 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 <ref name= "liu"/>. TYRP1 is found only in the membrane of mature stage III and IV melanosomes <ref name="ghanem"/>.

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 [https://www.uniprot.org/uniprot/P40126 TYRP2] activity <ref name= "koba"/>. The activity of the TYRP1 enzyme increase when the serine residues in position 505 and 509 are phosphorylated <ref name= "liu"/>. 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 <ref name= "box"/>.  

In addition, the [https://www.uniprot.org/uniprot/P07147 mouse homolog of the TYRP1] is involved in melanocytes differenciation too. Therefore, it could be used as a differentiation marker <ref name= "vija"/>. 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.  

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 <ref name="ghanem"/>. Therefore, the level of expression of TYRP1 mRNA is prognostic  marker <ref name= "journe"/>.

<ref name= "box"/> 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 

<ref name="chen"/> 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