Sandbox TYRP1

From Proteopedia

Revision as of 22:05, 12 January 2020

Tyrosinase related protein 1 (5M8L)

Structural highlights

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.^[1] The next part of the sequence is composed of a transmembrane alpha helix followed by a short cytoplasmic sequence on the C-terminal chain. ^[2]

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.^[1]

The active site

The active site is delimited by four helice and contain the binuclearmetal binding site. (image à faire)

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.^[2]

(Image à faire reaction chimique)

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 ^[1] 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.^[1] After that there is a transmembrane alpha helix followed by a short cytoplasmic sequence on the C-terminal chain. ^[2]

(image à faire)

These three proteins share similar active sites. Metal ions interact with three histidines.

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

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. ^[2]

References

^[1] 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

^[2] 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