Sandbox Reserved 1097: Difference between revisions

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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 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 has an epidermal growth factor‐like fold. This previous domain strongly interact with the tyrosinase-like subdomain (127-477) 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 ~~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"/>

The cystein-rich domain (25-126) 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). This previous domain strongly interact with the tyrosinase-like subdomain (127-477) 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 stabilize by three (42-65/56-99/101-110) 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"/>

The tyrosinase-like subdomain is composed of four helix bundle connected by long loops and stabilized by two disulfide bonds(C258–C261 and C290–C303). ~~this~~ domain ~~interact~~ with rich-cysteine domain by three insertions located on the same side of tyrosinase-like subdomain (residues 155–182, 199–204, and 291–300)

The tyrosinase-like subdomain is composed of four helix bundle connected by long loops and stabilized by two disulfide bonds(C258–C261 and C290–C303). This domain interacts with rich-cysteine domain by three insertions located on the same side of tyrosinase-like subdomain (residues 155–182, 199–204, and 291–300)

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 is delimited by four ~~helice~~ and ~~contain~~ the ~~binuclearmetal~~ binding site.

The active site 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 copper-binding site of Tyrosinases. The two 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 have no significant affect on TYRP1 activity.

The crystal structure of TYRP1 shows that TYRP1 can bind tyrosine, mimosine (DOPA equivalent), kojic acid, tropolone. These substrates 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 and ARG374 and Ser 394.

(image à faire)

Sandbox Reserved 1097: Difference between revisions

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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 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 has an epidermal growth factor‐like fold. This previous domain strongly interact with the tyrosinase-like subdomain (127-477) 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 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"/>
+The cystein-rich domain (25-126) 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). This previous domain strongly interact with the tyrosinase-like subdomain (127-477) 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 stabilize by three (42-65/56-99/101-110) 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"/>
-The tyrosinase-like subdomain is composed of four helix bundle connected by long loops and stabilized by two disulfide bonds(C258–C261 and C290–C303). this domain interact with rich-cysteine domain by three insertions located on the same side of tyrosinase-like subdomain (residues 155–182, 199–204, and 291–300)
+The tyrosinase-like subdomain is composed of four helix bundle connected by long loops and stabilized by two disulfide bonds(C258–C261 and C290–C303). This domain interacts with rich-cysteine domain by three insertions located on the same side of tyrosinase-like subdomain (residues 155–182, 199–204, and 291–300)
 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 is delimited by four helice and contain the binuclearmetal binding site.
+The active site 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 copper-binding site of Tyrosinases. The two 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 have no significant affect on TYRP1 activity.
+The crystal structure of TYRP1 shows that TYRP1 can bind tyrosine, mimosine (DOPA equivalent), kojic acid, tropolone. These substrates 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 and ARG374 and Ser 394.
 (image à faire)