BPS2026 – Cryo-EM structure reveals Na-dependent mechanism of human OCA2

Oculocutaneous albinism type 2 (OCA2) is an autosomal recessive disorder caused by mutations of the OCA2 gene, which is characterized by reduced formation of melanin pigment in the skin, hair, and eyes, and increased susceptibility to skin cancers. The OCA2 gene encodes the P protein, a transmembrane protein expressed in melanosomes of melanocytes, where it regulates the level of eumelanin. Numerous mutations of OCA2 have been reported in humans and animals, resulting in complete or partial albinism. Yet, the precise function and mechanism of OCA2 remain unclear. Here, we present the cryo-electron microscopy structures of the human OCA2 in detergent micelles and nanodiscs. These structures reveal the SLC13 family fold, comprising a scaffold and transport domain with additional luminal and cytosolic domains. Furthermore, we identified two Na-binding sites, corroborated by molecular dynamics studies and thermal-shift binding assays. Movements of transmembrane helices regulate the compactness and accessibility of the binding sites.