Membrane transport proteins in melanosomes: Regulation of ions for pigmentation

Abstract

Melanosomes are unique organelles in melanocytes that produce melanin, the pigment for skin, hair, and eye color. Tyrosinase is the essential and rate-limiting enzyme for melanin production, that strictly requires neutral pH for activity. pH maintenance is a result of the combinational function of multiple ion transport proteins. Thus, ion homeostasis in melanosomes is crucial for melanin synthesis. Defect of the ion transport system causes various pigmentation phenotypes, from mild effect to severe disorders such as albinism. In this review, we summarize the up-to-date knowledge of the ion transport system, such as transport function, structure, and the physiological roles and mechanisms of the ion transport proteins in melanosomes. In addition, we propose a model of melanosomal ion transport system-how the functional coupling of multiple transport proteins modulates and maintains ion homeostasis. We discuss melanin synthesis in terms of the ion transport system.

Chemical and biochemical control of skin pigmentation with special emphasis on mixed melanogenesis

“…Regardless of the final pH set point, melanosomal pH is a balance between increased melanosomal H + concentration from proton pumps and the activity of a variety of ion channels and transporters which control the electrochemical gradient. We will discuss the established proteins which regulate melanosomal pH and the mechanisms that regulate the melanosomal pH set point (Table 1, also reviewed in Wiriyasermkul et al., 2020).…”

“…TPC2 mutations or loss is not associated with any pigment diseases; however, polymorphisms in the protein are associated with hair color and UV sensitivity mostly in Icelandic and Dutch individuals (Böck et al., 2021; Chao et al., 2017; Sulem et al., 2008) (Table 1). The proposed interplay between the above proteins in regulating melanosomal pH was recently reviewed in the context of other melanosome proteins highlighting the role of other ions and pathogenic mutations/polymorphisms in pigmentation (Wiriyasermkul et al., 2020).…”

A new type of oculocutaneous albinism with a novel OCA2 mutation

“…TYR is the key enzyme for melanogenesis which is solely dependent on neutral pH. Ion transport proteins such as OCA2 , SLC45A2 , and TPC2 function together to promote TYR function in a so called “combinational function of ion transport proteins” for the maintenance of pH [ 14 ]. OCA2 induces large outward Cl − conductance which is essential for maintaining neutral pH for melanosomes [ 14 ].…”

ATP7A-Regulated Enzyme Metalation and Trafficking in the Menkes Disease Puzzle

“…Tyrosinase (TYR) catalyzes the first two steps in melanogenesis from tyrosine to DOPA and to dopaquinone. Tyrosine oxidation is rate-limiting followed by ER polymerization reactions [ 201 , 202 ] catalyzed by two members of tyrosinase-related proteins TYRP1 and TYRP2 [ 203 ].…”