Sandbox TYRP1: Difference between revisions
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=== Role in melanocytes === | === Role 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 [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 | 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 explained by the fact that the nature of ions in the active site is different. Indeed, two Zn2+ ions bound the active site of the TYRP1 enzyme instead of two Cu2+, which are responsible for a different activity <ref name= "lai"/>. 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.<ref name="Xlai"/> 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. | 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. | ||
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== Structural highlights == | == Structural highlights == | ||
=== Main domains and lattices === | === Main 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.<ref name=" | 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.<ref name="Xlai">[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]</ref> The next part of the sequence is composed of a transmembrane alpha helix followed by a short cytoplasmic sequence on the C-terminal chain. <ref name = "decker"> [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]</ref> | ||
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.<ref name=" | 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.<ref name="Xlai"/> | ||
TYRP1 has six sites of N-glygosylation which are important for maturation of the protein (Asn 96, 104,181,304,350,385). On our 3D structure all these sites are glycosylated. | |||
The crystal structure of TYRP1 shows that TYRP1 can bind tyrosine, mimosine, kojic acid, tropolone. These substrates can bind to the enzyme thanks to aromatic stacking interactions with H381. The keto and hydroxy groups interact with Zinc ions and some hydrogen bonds are created with S394. | |||
=== The active site === | === The active site === | ||
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== Comparison between enzymes of Tyrosinase family == | == Comparison 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.<ref name = "decker"/> | 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.<ref name = "decker"/>. 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. | ||
(Image à faire reaction chimique) | (Image à faire reaction chimique) | ||
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==== 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 <ref name=" | 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 <ref name="Xlai"/> | ||
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.<ref name=" | 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.<ref name="Xlai"/> | ||
After that there is a transmembrane alpha helix followed by a short cytoplasmic sequence on the C-terminal chain. <ref name = "decker"/> | After that there is a transmembrane alpha helix followed by a short cytoplasmic sequence on the C-terminal chain. <ref name = "decker"/> | ||
(image à faire) | (image à faire) | ||
According to crystal knowledges, it is said that TYRP1 and TYR can bind the same substrats. | |||
The three enzymes have several sites of N-glycosylation which are important 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. <ref name="Xlai"/> | |||
These three proteins share similar active sites. Metal ions interact with three histidines. | These three proteins share similar active sites. Metal ions interact with three histidines. | ||
==== Differences: ==== | ==== Differences: ==== | ||
The main difference between these three | The main difference between these three enzyme 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. | ||
Contrary to TYRP1 and TYRP2, TYR contains six sites of N-glycosylation. | |||
Interet des 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. <ref name = "decker"/> | 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. <ref name = "decker"/> | ||
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<ref name= "vija"/> Vijayasaradhi S., Bouchard B., Houghton A.N., 1990. The melanoma antigen gp75 is the human homolog of the mouse b (brown) locus gene product. J. Exp. Med.. 171, 1375–1380 PMCID:PMC2187848 PMID:2324688 https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC2187848&blobtype=pdf | <ref name= "vija"/> Vijayasaradhi S., Bouchard B., Houghton A.N., 1990. The melanoma antigen gp75 is the human homolog of the mouse b (brown) locus gene product. J. Exp. Med.. 171, 1375–1380 PMCID:PMC2187848 PMID:2324688 https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC2187848&blobtype=pdf | ||
<ref name=" | <ref name="Xlai"/> 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 | ||
