Functional analysis of human tyrosinase and OCA1 associated mutations.

Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disorder caused by mutations in the tyrosinase gene. OCA1 exists in two forms: OCA1A and OCA1B. OCA1A is caused by a full loss of the human tyrosinase protein (Tyr), leading to an absence of pigment in skin, hair, and eyes, while OCA1B has reduced Tyr catalytic activity and pigment. The current understanding of the disease is hampered by the absence of information regarding the alterations of protein structure and the effects leading to either form of OCA1. Here, we used computational methods to find a general mechanism for establishing this link. Tyr and mutant variants were built through homology modeling, glycosylated , minimized, and simulated using 100 ns molecular dynamics in water. For OCA1B mutants, cavity size is linked to ΔΔG values for mutants, suggesting that partial loss of Tyr is associated with the destabilizing effect of the EGF-like domain movement. In OCA1A, active site mutation simulations indicate that the absence of O leads to protein instability. OCA1B mutants are described in severity by the size of the cavity within the EGF-Tyr interface, while active site OCA1A mutants are unable to fully coordinate copper, leading to an absence of O and Tyr instability. In patients with known genotypes, free energy changes may help identify the severity of the disease by assessing either the allosteric effect of the EGF-Tyr cavity in OCA1B or the active site instability in OCA1A.