Structural basis of receptor-mediated cellular vitamin A uptake

受体介导的细胞维生素 A 摄取的结构基础

• 批准号: 9898381
• 负责人: Filippo Mancia
• 金额: $ 49.82万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9898381
• 关键词: 11 cis Retinal; All-Trans-Retinol; Anophthalmos; Binding; Biological Assay; Biological Process; Biophysics; Blindness; Blood Circulation; Calmodulin; Cell membrane; Cells; Cellular Retinol Binding Protein; Complex; Coupled; Cryoelectron Microscopy; Data; Defect; Dependence; Development; Diet; Disease; Enzymes; Equilibrium; Esters; Exhibits; Eye; Fasting; Genes; Genetic Transcription; Health; Human; Hydrophobicity; Intake; Integral Membrane Protein; Knockout Mice; Lead; Length; Ligands; Link; Liver; Mammals; Mediating; Membrane; Metabolism; Microphthalmos; Modeling; Molecular; Molecular Conformation; Molecular Probes; Mutagenesis; Mutation; Names; Nuclear Receptors; Nutrient; Pathology; Pathway interactions; Peptides; Peripheral; Phenotype; Physiological; Positioning Attribute; Proteins; Protomer; Resolution; Retinal Pigments; Retinaldehyde; Retinoids; Retinol Binding Proteins; Roentgen Rays; Role; Route; Signaling Molecule; Site; Structure; System; Techniques; Technology; Testing; Thermodynamics; Time; Tissues; Tretinoin; Vision; Visual system structure; Vitamin A; Vitamins; Woods syndrome; Zebrafish; base; design; design and construction; dimer; disease-causing mutation; experimental study; extracellular; insight; lecithin-retinol acyltransferase; malformation; mutant; new therapeutic target; particle; protein complex; receptor; retinol binding protein receptor; structured data; uptake; visual cycle

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.

维生素A是所有哺乳动物必需的营养素。许多生物过程，包括最重要的视觉，都至关重要地依赖于它的充足供应来维持正常功能。维生素A代谢的改变可导致广泛的眼部缺陷并导致失明。