Genetic mutations disrupt the coordinated mode of tyrosinase's intra-melanosomal domain.

Abstract

Oculocutaneous albinism type 1 is a genetic disorder caused by the disruption of tyrosinase activity in the melanogenesis pathway. The tyrosinases intramelanosomal domain can be subdivided into the catalytic and Cys-rich subdomains, integral for protein stability and catalytic activity. To understand the motions in the tyrosinase intra-melanosomal subdomains and their link to its catalytic activity, we perform essential dynamics on homology models for tyrosinase and the mutant variants R217Q, R402Q, and R217Q/R402Q. Dimensional reduction techniques, such as Principal Component Analysis (PCA), are fundamental to systematically comprehending collective motions in protein structure. The alpha-carbon atomic coordinates for all residues across a 100 ns molecular dynamic trajectory were input into the PCA function, and the results were analyzed alongside correlated movements and free energy profiles for each protein structure. The PCA-identified coordinated movement underlying the stable conformations of wild-type tyrosinase arises within the H9 and H10 helices, which are proximal to the flexible tunnel system and the interface of the catalytic and Cys-rich subdomains. In contrast, genetic mutations R217Q and R217Q/R402Q disrupt the coordinated movement of the tyrosinase intra-melanosomal domain, indicating a cause of mutant variant instability. Statement of Importance for Broad AudienceThis study applies molecular dynamics and PCA to the coordinated movements underlying tyrosinase protein stability. The collective motions within the core alpha helix bundle were found in the atomic model of tyrosinase. In OCA1-causing mutant variants, collective motions are lost, suggesting a role of helices in maintaining the stability of wild-type protein. Furthermore, we highlight the proximity of alpha-helices H9 and H10 to the interface of the catalytic and Cys-rich subdomains, which may serve as a potential binding site for targeting by small chaperone molecules to stabilize wild type tyrosinase.