Abstract
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 individual missense mutations causing single nucleotide variants and polymorphisms (SNVs) in TYR. We previously showed that two TYR homologues, TYRP1 and TYRP2, modulate TYR activity and stabilize the TYR protein. Accordingly, to investigate whether TYR, TYRP1, and TYRP2 are biophysically compatible with various heterocomplexes, we computationally docked a high-quality 3D model of TYR to the crystal structure of TYRP1 and to a high-quality 3D model of TYRP2. Remarkably, 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. Hence, the 3D models are compatible with a heterotrimeric TYR-TYRP1-TYRP2 complex. In addition, this heterotrimeric TYR-TYRP1-TYRP2 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. Finally, pathogenic TYR mutations causing OCA1A, which also destabilize 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. While this complex may be difficult to detect in vitro, due to the complex environment of the vertebrate cellular membranous system, our results support the existence of a heterotrimeric complex in melanogenesis.
Highlights
Tyrosinase (TYR) catalyzes three reactions during melanin synthesis in mammalian skin, eyes, and other organs
The results strongly suggest the existence of a membrane-associated heterotrimeric TYR-TYRP1TYRP2 complex, exhibiting an unoccupied protein surface decorated with OCA1A mutations
In order to determine if TYR and the TRPs form molecular surfaces that are complementary to each other in pairs or trimers in terms of shape, electrostatics, and other physics-based properties, we built maximally accurate, energy minimized models of TYR and TYRP2 based on their homology to the TYRP1 crystal structure (PDB: 5M8L; resolution 2.35 A) (Lai et al, 2017)
Summary
Tyrosinase (TYR) catalyzes three reactions during melanin synthesis in mammalian skin, eyes, and other organs. Efficient maturation of the TYR protein ensures stability, enzyme activity and delivery to melanosomes where melanin is produced and deposited. Impaired TYR maturation is common to several forms of the group of genetic disorders known as oculocutaneous albinism (OCA) in humans. Mutations in the TYR gene itself, many of which cause protein misfolding with attendant inability to exit the endoplasmic reticulum (ER) (Berson et al, 2000; Toyofuku et al, 2001a; Chaki et al, 2010), result in OCA type 1 (OCA1A). Less severe TYR mutations cause partial loss of function and reduced protein folding efficiency (OCA1B) (Toyofuku et al, 2001a). TYR is retained in the ER in OCA2 (Chen et al, 2002) [OCA2 gene mutations (Kedda et al, 1994)], OCA3 (Toyofuku et al, 2001b) [TYRP1 mutations (Manga et al, 1997)] and OCA4 (Costin et al, 2003) [SLC45A2 mutations (Newton et al, 2001)]
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