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9.B.423. The Tysrosinase (TYR) Family 

Tyrosinase (TYR) is a copper-containing monooxygenase central to the function of melanocytes. Alterations in its expression or activity contribute to variations in skin, hair and eye color, and underlie a variety of pathogenic pigmentary phenotypes, including several forms of oculocutaneous albinism (OCA). Many of these phenotypes are linked to missense mutations causing single nucleotide variants and polymorphisms (SNVs) in TYR. Two TYR homologues, TYRP1 and TYRP2, modulate TYR activity and stabilize the TYR protein. Lavinda et al. 2021 docked a 3D model of TYR to the crystal structure of TYRP1 and to a 3D model of TYRP2. The resulting TYR-TYRP1 heterodimer was complementary in structure and energy with the TYR-TYRP2 heterodimer, with TYRP1 and TYRP2 docking to different adjacent surfaces on TYR that apposed a third realistic protein interface between TYRP1-TYRP2. The 3D models are compatible with a heterotrimeric TYR-TYRP1-TYRP2 complex which positioned the C-terminus of each folded enzymatic domain in an ideal position to allow their C-terminal transmembrane helices to form a putative membrane embedded three-helix bundle. Pathogenic TYR mutations causing OCA1A (TC# 2.A.45.2.1), which also destabilizes TYR biochemically, cluster on an unoccupied protein interface at the periphery of the heterotrimeric complex, suggesting that this may be a docking site for OCA2, an anion channel. Pathogenic OCA2 mutations result in similar phenotypes to those produced by OCA1A TYR mutations (Lavinda et al. 2021). 

 

References associated with 9.B.423 family:

Hutchinson, J.A., I.W. Hamley, C.J.C. Edwards-Gayle, V. Castelletto, C. Piras, R. Cramer, R. Kowalczyk, J. Seitsonen, J. Ruokolainen, and R.P. Rambo. (2019). Melanin production by tyrosinase activity on a tyrosine-rich peptide fragment and pH-dependent self-assembly of its lipidated analogue. Org Biomol Chem 17: 4543-4553. 30994696
Kenny, E.E., N.J. Timpson, M. Sikora, M.C. Yee, A. Moreno-Estrada, C. Eng, S. Huntsman, E.G. Burchard, M. Stoneking, C.D. Bustamante, and S. Myles. (2012). Melanesian blond hair is caused by an amino acid change in TYRP1. Science 336: 554. 22556244
Lai, X., H.J. Wichers, M. Soler-Lopez, and B.W. Dijkstra. (2017). Structure of Human Tyrosinase Related Protein 1 Reveals a Binuclear Zinc Active Site Important for Melanogenesis. Angew Chem Int Ed Engl 56: 9812-9815. 28661582
Lai, X., H.J. Wichers, M. Soler-Lopez, and B.W. Dijkstra. (2018). Structure and Function of Human Tyrosinase and Tyrosinase-Related Proteins. Chemistry 24: 47-55. 29052256
Lavinda, O., P. Manga, S.J. Orlow, and T. Cardozo. (2021). Biophysical Compatibility of a Heterotrimeric Tyrosinase-TYRP1-TYRP2 Metalloenzyme Complex. Front Pharmacol 12: 602206. 33995009
Olivares, C. and F. Solano. (2009). New insights into the active site structure and catalytic mechanism of tyrosinase and its related proteins. Pigment Cell Melanoma Res 22: 750-760. 19735457
Rooryck, C., C. Roudaut, E. Robine, J. Müsebeck, and B. Arveiler. (2006). Oculocutaneous albinism with TYRP1 gene mutations in a Caucasian patient. Pigment Cell Res 19: 239-242. 16704458