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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 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 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>
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 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 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''' ''(25-126)''  
* '''The cystein-rich subdomain''' ''(25-126)''  
The cystein-rich domain has an epidermal growth factor‐like fold formed by two pairs of short antiparallel beta-strands (62-66/98-102 and 116-118/124-126)<ref name= "lai"/> . This previous domain strongly interact with the tyrosinase-like subdomain by the lastloop 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. This domain is stabilized by three (42-65/56-99/101-110) disulfide bounds and is located at the opposite of the active site. It is said that the cystein-rich domain might help to the formation of a complexe between TYR and TYRP2.<ref name="Xlai"/><ref name= "lai"/>  
The cystein-rich domain has an epidermal growth factor‐like fold formed by two pairs of short antiparallel beta-strands (62-66/98-102 and 116-118/124-126)<ref name= "lai"/> . This previous domain strongly interact with the tyrosinase-like subdomain by the lastloop 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. This domain is stabilized by three (42-65/56-99/101-110) disulfide bounds and is located at the opposite of the active site. It is said that the cystein-rich domain might help to the formation of a complexe between TYR and TYRP2.<ref name="Xlai"/><ref name= "lai"/>  


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(Image à faire reaction chimique)  
(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 <ref name="Xlai"/>
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).<ref name = "decker"/> 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.<ref name= "lai"/>
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 cystein-rich 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"/>


(image à faire)
(image à faire)
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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"/>
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"/>


==== 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. 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's contains only one molecule of water and a substrate which are interacting with only one Zn2+ ion. However, no 3D-structure of TYRP2 is now available so the exact coordination of metal ions in the active site stay unclear.<ref name="Xlai"/>
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's contains only one molecule of water and a substrate which are interacting with only one Zn2+ ion. However, no 3D-structure of TYRP2 is now available so the exact coordination of metal ions in the active site stay unclear.<ref name="Xlai"/>
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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"/>
 
==Diseases==
===Oculocutaneous 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.<ref name = "grønskov"/> 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.<ref name= "lai"/> 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.<ref name = "grønskov"/>
==References==
==References==
<ref name="ghanem"/> Ghanem, G., and Fabrice, J. Tyrosinase related protein 1 (TYRP1/gp75) in human cutaneous melanoma. Molecular Oncology, 2011,5(2): 150–155. PMID: 21324755 DOI: 10.1016/j.molonc.2011.01.006 https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/j.molonc.2011.01.006
<ref name="ghanem"/> Ghanem, G., and Fabrice, J. Tyrosinase related protein 1 (TYRP1/gp75) in human cutaneous melanoma. Molecular Oncology, 2011,5(2): 150–155. PMID: 21324755 DOI: 10.1016/j.molonc.2011.01.006 https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/j.molonc.2011.01.006
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<ref name= "journe"/> Journe F. ,  Boufker H. Id.,  Van Kempen L.,  Galibert M-D., Wiedig M. ,  Salès F.,  Theunis A.,  Nonclercq D.,  Frau A.,  Laurent G.,  Awada A. and  Ghanem G., 2011. TYRP1 mRNA expression in melanoma metastases correlates with clinical outcome. Br J Cancer. 105(11): 1726–1732. PMID:22045183 DOI:10.1038/bjc.2011
<ref name= "journe"/> Journe F. ,  Boufker H. Id.,  Van Kempen L.,  Galibert M-D., Wiedig M. ,  Salès F.,  Theunis A.,  Nonclercq D.,  Frau A.,  Laurent G.,  Awada A. and  Ghanem G., 2011. TYRP1 mRNA expression in melanoma metastases correlates with clinical outcome. Br J Cancer. 105(11): 1726–1732. PMID:22045183 DOI:10.1038/bjc.2011
    
    
<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 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 name = "grønskov"/> Grønskov K, Ek J, Brondum-Nielsen K. Oculocutaneous albinism. Orphanet J Rare Dis. 2007 Nov 2;2:43. doi: 10.1186/1750-1172-2-43. PMID: 17980020; PMCID: PMC2211462. https://www.ncbi.nlm.nih.gov/pubmed/17980020?dopt=Abstract
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