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首页> 外文期刊>Pigment cell research >The melanosomal/lysosomal protein OA1 has properties of a G protein-coupled receptor
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The melanosomal/lysosomal protein OA1 has properties of a G protein-coupled receptor

机译：黑素体/溶酶体蛋白OA1具有G蛋白偶联受体的特性

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摘要

The protein product of the ocular albinism type 1 gene, named OA1, is a pigment cell-specific integral membrane glycoprotein, localized to melanosomes and lysosomes and possibly implicated in melanosome biogenesis. Although its function remains unknown, we previously showed that OA1 shares structural similarities with G protein-coupled receptors (GPCRs). To ascertain the molecular function of OA1 and in particular its nature as a GPCR, we adopted a heterologous expression strategy commonly exploited to demonstrate GPCR-mediated signaling in mammalian cells. Here we show that when expressed in COS7 cells OA1 displays a considerable and spontaneous capacity to activate heterotrimeric G proteins and the associated signaling cascade. In contrast, OA1 mutants carrying either a missense mutation or a small deletion in the third cytosolic loop lack this ability. Furthermore, OA1 is phosphorylated and interacts with arrestins, well-established multifunctional adaptors of conformationally active GPCRs. In fact, OA1 colocalizes and coprecipitates with arrestins, which downregulate the signaling of OA1 by specifically reducing its expression levels. These findings indicate that heterologously expressed OA1 exhibits two fundamental properties of GPCRs, being capable to activate heterotrimeric G proteins and to functionally associate with arrestins, and provide proof of principle that OA1 can actually function as a canonical GPCR in mammalian cells.
机译：眼白化病1型基因的蛋白质产物称为OA1，是色素细胞特异性整合膜糖蛋白，定位于黑素体和溶酶体，可能与黑素体的生物发生有关。尽管其功能仍然未知，但我们之前已经证明OA1与G蛋白偶联受体（GPCR）具有结构相似性。为了确定OA1的分子功能，尤其是其作为GPCR的性质，我们采用了一种异源表达策略，该策略通常用于证明GPCR介导的哺乳动物细胞信号传导。在这里，我们表明，当在COS7细胞中表达时，OA1表现出相当大的自发激活异三聚体G蛋白和相关信号传导级联的能力。相反，在第三个胞质环中携带错义突变或少量缺失的OA1突变体缺乏这种能力。此外，OA1被磷酸化并与抑制蛋白相互作用，而抑制蛋白是构象活性GPCR的公认的多功能衔接子。实际上，OA1与抑制蛋白共定位并共沉淀，后者通过特异性降低其表达水平来下调OA1的信号传导。这些发现表明，异源表达的OA1表现出GPCR的两个基本特性，能够激活异源三聚体G蛋白和功能与抑制蛋白结合，并提供原理证明OA1实际上可以在哺乳动物细胞中起典型的GPCR作用。

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