Structure of Human Tyrosinase Related Protein 1 Reveals a Binuclear Zinc Active Site Important for Melanogenesis

Abstract

Tyrosinase‐related protein 1 (TYRP1) is one of three tyrosinase‐like glycoenzymes in human melanocytes that are key to the production of melanin, the compound responsible for the pigmentation of skin, eye, and hair. Difficulties with producing these enzymes in pure form have hampered the understanding of their activity and the effect of mutations that cause albinism and pigmentation disorders. Herein we show that the typical tyrosinase‐like subdomain of TYRP1 contains two zinc ions in the active site instead of copper ions as found in tyrosinases, which explains why TYRP1 does not exhibit tyrosinase redox activity. In addition, the structures reveal for the first time that the Cys‐rich subdomain, which is unique to vertebrate melanogenic proteins, has an epidermal growth factor‐like fold and is tightly associated with the tyrosinase subdomain. Our structures suggest that most albinism‐related mutations of TYRP1 affect its stability or activity.

Protein Stability and Functional Characterization of Intra-Melanosomal Domain of Human Recombinant Tyrosinase-Related Protein 1

“…Although Tyr's catalytic function tends to be the focus of melanogenesis, there are two other tyrosinase-related proteins, Tyrp1 and Tyrp2, which have roles that have yet to be clearly defined in humans. The crystal structure of Tyrp1 is currently available [1]. All human tyrosinases share a remarkable number of characteristics including melanocyte-specific expression, transmembrane motifs, localization to the melanosome, an EGF protein interaction motif, similar N-glycosylation sites, and similar protein sequences of catalytic domain.…”

Insect cuticular melanins are distinctly different from those of mammalian epidermal melanins

“…But the existence of DHICA oxidase activity in human is uncertain (Boissy, Sakai, Zhao, Kobayashi, & Hearing, 1998;Lai, Wichers, Soler-Lopez, & Dijkstra, 2017). Oxidative polymerization of DHICA produces the light brown eumelanin, while oxidative polymerization of DHI produces brown to black eumelanin.…”

In-silico Screening of Selected Apiaceae Plants as Melanogenesis Inhibitors and their Predicted Skin Permeability

“…4 (1), 51-61, 2020 (Fig.3), it was found that these standard melanogenesis inhibitors were successfully docked within the active site of the novel target enzyme. That was evidenced by the presence of the two zinc atoms which are essential for the activity (Lai et al, 2017). Kojic acid ( Fig.3 B and D); the cocrystallized ligand, formed hydrogen bond with Ser394 residue and numerous polar interactions with Hid192, 215, 377, 381 (Histidine with hydrogen on the delta nitrogen), in addition to hydrophobic interactions with Phe400 and Leu382.…”

“…the specific melanogenic function of TRP1 is the oxidation of 5,6-dihydroxyindole-2-carboxylic acid to a carboxylated indole-quinone at a downstream point in the melanin biosynthetic pathway (Kobayashi et al, 1994). TYRP1 contains 4 conserved regions: the signal peptide, the intramelanosomal domain that is subdivided into the Cys-rich and the tyrosinase-like subdomains, the transmembrane α-helix, and the cytoplasmic domain (Lai et al, 2017).…”

“…The second enzyme is tyrosinase-related protein 2 (TYRP2) which is a tautomerase enzyme and the third one is tyrosinaserelated protein 1 (TYRP1) which was found to be overexpressed in melanocytes in case of malignant melanoma. All these tyrosinase enzyme family members are metal-containing glycoproteins localized in melanosomes where the melanin biosynthesis occurs (Lai et al, 2017).…”