Structural basis of receptor-mediated cellular vitamin A uptake

维生素A是所有哺乳动物的必需营养素。许多生物过程，包括最重要的视觉，都严重依赖于其适当功能的充足供应。维生素A代谢的改变会导致多种眼部缺陷，并导致失明。 维生素A醇(维生素A酒精)是空腹状态下循环中的主要维生素A形式。在需要的时候(即在没有摄入维生素A的情况下)，为了将维生素A分配到目标外周组织，视黄醇从肝脏在血液中释放，视黄醇是维生素A的主要储存部位，与视黄醇结合蛋白(RBP)结合。在细胞内，视黄醇结合特定的细胞内载体，即细胞视黄醇结合蛋白，它是活性维生素A形式的前体：对视力至关重要的视黄醛，以及调节数百个目标基因转录的特定核受体的配体维甲酸。视黄醇是如何从视黄醇-RBP复合体中释放出来并被细胞内化的，几十年来一直是争论的主题。STRA6是RBP的质膜受体，于2007年被发现。然而，其行动机制仍然难以捉摸，尤其是由于缺乏任何结构性信息。 在这里，我们介绍了用单粒子低温电子显微镜测得的分辨率为4.2？的STRA6的结构。STRA6是一种二聚体，每个原型提供九个跨膜和一个水平的膜内螺旋，位于二聚体界面的核心。出乎意料的是，每个原型的C末端都以一种紧凑的、非正则的排列方式与钙调蛋白紧密结合。该结构提示了视黄醇可能与胞外和胞内载体相互作用的部位，以及视黄醇内化的方式。STRA6的原子模型提供了一个模板，指导我们在分子水平上了解该蛋白质的功能，并进一步研究其生理作用。

Vitamin A is an essential nutrient for all mammals. Many biological processes, including and foremost vision, are crucially dependent on its adequate supply for proper function. Alterations of vitamin A metabolism can result in a wide spectrum of ocular defects and lead to blindness. Retinol (vitamin A alcohol) is the predominant circulating vitamin A form in the fasting state. In times of need (i.e. in the absence of dietary vitamin A intake), in order to distribute vitamin A to the target peripheral tissues, retinol is released in the bloodstream from the liver, the main body storage site of the vitamin, bound to retinol-binding protein (RBP). Inside the cells, retinol binds specific intracellular carriers, namely cellular retinol-binding proteins, and it serves as a precursor for the active vitamin A forms: retinaldehyde, critical for vision, and retinoic acid, the ligand for specific nuclear receptors that regulate the transcription of hundreds of target genes. How retinol is released from the retinol-RBP complex and internalized by the cell has been subject of debate for decades. STRA6, the putative plasma membrane receptor for RBP, was identified in 2007. However, its mechanism of action has remained elusive, not least due to the absence of any structural information. Here we present the structure of STRA6 determined to 4.2 Å resolution by single-particle cryo-electron microscopy. STRA6 is a dimer, with each protomer contributing nine transmembrane and a horizontal intramembrane helix that is positioned at the core of the dimer interface. Unexpectedly, the C-terminus of each protomer is tightly bound to calmodulin in a compact, non-canonical arrangement. The structure suggests possible sites for interaction with extracellular and intracellular carriers for retinol, and modes for internalization of retinol. The atomic model of STRA6 provides a template to guide our understanding at a molecular level on how this protein may function, and to further investigate its physiological role.