Figure 3.

Schematic representation of the biogenesis of an eumelanosome. The development and maturation of melanosomes proceeds through four stages, which can be grouped into two unpigmented (stages I and II) and pigmented (stages III and IV) steps. Melanosomes are assembled in the perinuclear region, near the Golgi stacks, receiving the enzymatic and structural proteins required for melanogenesis. In Stage I, immature melanosomes are spherical, vacuolar domains of early endosomes that harbour intralumenal vesicles formed by invagination of the limiting membrane. In Stage II, pre-melanosomes are characterized by a fully formed melanosome matrix, where PMEL fibrils are organized into arrays of parallel sheets, transforming the spherical Stage I melanosomes into elongated, elliptical organelles. The formation of PMEL fibrils segregates the melanosomal from the endosomal pathways, which seems to involve GPR143 and MLANA. In Stage III, melanogenesis starts with the pigment being regularly and uniformly synthesized on the fibrillar matrix, which causes the darkening and thickening of the matrix fibrils. By Stage IV, the melanosomes are saturated with melanin, in this case predominantly eumelanin, and the internal fibrillar structure becomes completely masked by the pigment; the mature melanosomes are ready to be transferred to adjacent keratinocytes. Melanogenic proteins are loaded into vesicular or tubular carriers for delivery into melanosomes through a process involving the fusion of their limiting membranes. The sorting and transport of melanogenic proteins involve multisubunit protein complexes, such as AP-1 and AP-3, as well as BLOC-1 and BLOC-2. AP-1/3: adaptor-related protein complex 1/3; ATP7A: ATPase copper transporting alpha; BLOC-1/2: biogenesis of lysosomal organelles complex 1/2; ER: endoplasmic reticulum; GPR143: G protein-coupled receptor 143; ILV: intralumenal vesicle; MITF: microphthalmia-associated transcription factor; MLANA: protein melan-a; OCA2: oculocutaneous albinism 2 protein; PMEL: premelanosome protein; TYR: tyrosinase; TYRP1: tyrosinase related protein 1.