Sandbox Reserved 1097: Difference between revisions
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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 <scene name='82/829350/Asymmetric_unit/1'>asymmetric unit</scene> of TYRP1. The 3D-structure of the biological unit represents only the amino acids between 25 and 470 of the sequence. | 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 <scene name='82/829350/Asymmetric_unit/1'>asymmetric unit</scene> 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.<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 α-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> | 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.<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 (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).<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 subdomain''' ''(25-126)'' | * '''The cystein-rich subdomain''' ''(25-126)'' | ||
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=== The active site === | === The active site === | ||
* '''Structure''' | * '''Structure''' | ||
[[Image:5m8l screenshot (1).png|thumb|center|upright=4.0|The active site of TYRP1, Blue: hydrogen bonds, Green: Pi interactions, Purple: Metal interactions, To see the 3D-structure of the activ site click there : https://www.rcsb.org/3d-view/5M8L?preset=ligandInteraction&sele=ZN]] | [[Image:5m8l screenshot (1).png|thumb|center|upright=4.0|The active site of TYRP1, Blue: hydrogen bonds, Green: Pi interactions, Purple: Metal interactions, To see the 3D-structure of the activ site click there : https://www.rcsb.org/3d-view/5M8L?preset=ligandInteraction&sele=ZN and select [ZN]516B in Ligands category]] | ||
<scene name='82/829350/Active_site/2'>The active site</scene> 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 [https://en.wikipedia.org/wiki/Copper_protein 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.<ref name= "lai"/> | <scene name='82/829350/Active_site/2'>The active site</scene> 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 [https://en.wikipedia.org/wiki/Copper_protein 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.<ref name= "lai"/> | ||
* '''Ligand interactions''' | * '''Ligand interactions''' | ||
The crystal structure of TYRP1 shows that TYRP1 can bind [https://en.wikipedia.org/wiki/Tyrosine tyrosine], [https://en.wikipedia.org/wiki/Mimosine mimosine] ([https://en.wikipedia.org/wiki/L-DOPA DOPA] equivalent), [https://en.wikipedia.org/wiki/Kojic_acid kojic acid], [https://pubchem.ncbi.nlm.nih.gov/compound/Tropolone 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, | The crystal structure of TYRP1 shows that TYRP1 can bind [https://en.wikipedia.org/wiki/Tyrosine tyrosine], [https://en.wikipedia.org/wiki/Mimosine mimosine] ([https://en.wikipedia.org/wiki/L-DOPA DOPA] equivalent), [https://en.wikipedia.org/wiki/Kojic_acid kojic acid], [https://pubchem.ncbi.nlm.nih.gov/compound/Tropolone 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 <scene name='82/829350/Interactions_active_site/1'>other interactions</scene> between these substrates and amino acids close to the active site. Tropolone has direct interactions with one of the Zn2+ ion because of its [https://en.wikipedia.org/wiki/Chelation 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.<ref name= "lai"/> | ||
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.<ref name = "decker"/> | 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.<ref name = "decker"/> | ||
== Comparison between enzymes of the Tyrosinase family == | == Comparison 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.<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:Melanin biosynthesis.jpg|thumb|right|upright=1.5|Melanin biosynthesis information extracted from https://reactome.org/PathwayBrowser/#/R-HSA-5662702]] 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.<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. | ||
==== Similarities ==== | ==== Similarities ==== | ||
