pH plays a crucial role for melanosome maturation and function. Melanosomal pH changes during maturation from very acidic in the early stages to neutral in late stages. Neutral pH is critical for providing optimal conditions for the rate-limiting, pH-sensitive melanin synthesizing enzyme tyrosinase (TYR). This dramatic change in pH is thought to result from the activity of several proteins that control melanosomal pH. Here, we investigated the pH-dependence of the stability of these proteins and compare it with the pH dependence of the stability of TYR. We confirmed that the pH-optimum of TYR is neutral, and we also found that proteins that are negative regulators of melanosomal pH also function optimally at neutral pH. In contrast, positive pH regulators tended to have an acidic pH-optimum. Building on previous work that demonstrated that pH-optima of stability and activity are correlated, our findings are consistent with the expected activity of positive and negative regulators. Thus, positive pH regulators are most active at low pH, while negative regulators are most active at high pH. Furthermore, we investigated the<br/>effects of disease-causing mutations on the pH-dependence of these proteins and show that a significant raction of these mutations perturb their pH dependence; this is particularly prominent for the OCA2 protein. In conclusion, melanosomal pH appears to affect the activity of multiple proteins beyond TYR.

Modeling pH-dependence of melanosome formation

ACS Spring Meeting 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.