scholarly journals Regulatory mechanism for the transmembrane receptor that mediates bidirectional vitamin A transport

2020 ◽  
Vol 117 (18) ◽  
pp. 9857-9864 ◽  
Author(s):  
Ming Zhong ◽  
Riki Kawaguchi ◽  
Brianna Costabile ◽  
Yuyan Tang ◽  
Jane Hu ◽  
...  
Keyword(s):  
Vitamin A ◽  
High Performance ◽  
Skin Diseases ◽  
Human Diseases ◽  
Retinol Binding Protein ◽  
Cell Surface Receptor ◽  
Major Protein ◽  
Associated Proteins ◽  
Surface Receptor ◽  
Vitamin A Transport

Vitamin A has diverse biological functions and is essential for human survival at every point from embryogenesis to adulthood. Vitamin A and its derivatives have been used to treat human diseases including vision diseases, skin diseases, and cancer. Both insufficient and excessive vitamin A uptake are detrimental, but how its transport is regulated is poorly understood. STRA6 is a multitransmembrane domain cell-surface receptor and mediates vitamin A uptake from plasma retinol binding protein (RBP). STRA6 can mediate both cellular vitamin A influx and efflux, but what regulates these opposing activities is unknown. To answer this question, we purified and identified STRA6-associated proteins in a native mammalian cell type that takes up vitamin A through STRA6 using mass spectrometry. We found that the major protein repeatedly identified as STRA6-associated protein is calmodulin, consistent with the cryogenic electron microscopy (cryo-EM) study of zebrafish STRA6 associated with calmodulin. Using radioactivity-based, high-performance liquid chromatography (HPLC)-based and real-time fluorescence techniques, we found that calmodulin profoundly affects STRA6’s vitamin A transport activity. Increased calcium/calmodulin promotes cellular vitamin A efflux and suppresses vitamin A influx through STRA6. Further mechanistic studies revealed that calmodulin enhances the binding of apo-RBP to STRA6, and this enhancement is much more pronounced for apo-RBP than holo-RBP. This study revealed that calmodulin regulates STRA6’s vitamin A influx or efflux activity by modulating its preferential interaction with apo-RBP or holo-RBP. This molecular mechanism of regulating vitamin A transport may point to new directions to treat human diseases associated with insufficient or excessive vitamin A uptake.

scholarly journals Vitamin A Transport and the Transmembrane Pore in the Cell-Surface Receptor for Plasma Retinol Binding Protein

PLoS ONE ◽  
2013 ◽  
Vol 8 (11) ◽  
pp. e73838 ◽  
Author(s):  
Ming Zhong ◽  
Riki Kawaguchi ◽  
Mariam Ter-Stepanian ◽  
Miki Kassai ◽  
Hui Sun
Keyword(s):  
Vitamin A ◽  
Cell Surface ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
Cell Surface Receptor ◽  
Surface Receptor ◽  
Plasma Retinol ◽  
Vitamin A Transport

scholarly journals Vitamin A Transport Mechanism of the Multitransmembrane Cell-Surface Receptor STRA6

Membranes ◽  
2015 ◽  
Vol 5 (3) ◽  
pp. 425-453 ◽  
Author(s):  
Riki Kawaguchi ◽  
Ming Zhong ◽  
Miki Kassai ◽  
Mariam Ter-Stepanian ◽  
Hui Sun
Keyword(s):  
Vitamin A ◽  
Cell Surface ◽  
Transport Mechanism ◽  
Cell Surface Receptor ◽  
Surface Receptor ◽  
Vitamin A Transport

The transfer of transthyretin and receptor-binding properties from the plasma retinol-binding protein to the epididymal retinoic acid-binding protein

2002 ◽  
Vol 362 (2) ◽  
pp. 265-271 ◽  
Author(s):  
Manickavasagam SUNDARAM ◽  
Daan M. F. van AALTEN ◽  
John B. C. FINDLAY ◽  
Asipu SIVAPRASADARAO
Keyword(s):  
Retinoic Acid ◽  
Binding Protein ◽  
Binding Pocket ◽  
Retinol Binding Protein ◽  
Cell Surface Receptor ◽  
Acid Binding Protein ◽  
The Family ◽  
Surface Receptor ◽  
A Cell ◽  
Plasma Retinol

Members of the lipocalin superfamily share a common structural fold, but differ from each other with respect to the molecules with which they interact. They all contain eight β-strands (A—H) that fold to form a well-defined β-barrel, which harbours a binding pocket for hydrophobic ligands. These strands are connected by loops that vary in size and structure and make up the closed and open ends of the pocket. In addition to binding ligands, some members of the family interact with other macromolecules, the specificity of which is thought to be associated with the variable loop regions. Here, we have investigated whether the macromolecular-recognition properties can be transferred from one member of the family to another. For this, we chose the prototypical lipocalin, the plasma retinol-binding protein (RBP) and its close structural homologue the epididymal retinoic acid-binding protein (ERABP). RBP exhibits three molecular-recognition properties: it binds to retinol, to transthyretin (TTR) and to a cell-surface receptor. ERABP binds retinoic acid, but whether it interacts with other macromolecules is not known. Here, we show that ERABP does not bind to TTR and the RBP receptor, but when the loops of RBP near the open end of the pocket (L-1, L-2 and L-3, connecting β-strands A—B, C—D and E—F, respectively) were substituted into the corresponding regions of ERABP, the resulting chimaera acquired the ability to bind TTR and the receptor. L-2 and L-3 were found to be the major determinants of the receptor- and TTR-binding specificities respectively. Thus we demonstrate that lipocalins serve as excellent scaffolds for engineering novel biological functions.

scholarly journals A Functional Binding Domain in the Rbpr2 Receptor is Required for Vitamin A Transport, Ocular Retinoid Homeostasis, and Photoreceptor Cell Survival in Zebrafish

2020 ◽  
Author(s):  
Ashish K. Solanki ◽  
Altaf A Kondkar ◽  
Joseph Fogerty ◽  
Yanhui Su ◽  
Seok-hyung Kim ◽  
...  
Keyword(s):  
Vitamin A ◽  
Cell Survival ◽  
Photoreceptor Cell ◽  
Binding Protein ◽  
Binding Domain ◽  
Human Vision ◽  
Retinol Binding Protein ◽  
Dietary Vitamin ◽  
Binding Residues ◽  
Vitamin A Transport

Dietary vitamin A/all-trans retinol/ROL plays a critical role in human vision. ROL circulates bound to the plasma retinol-binding protein (RBP4) as RBP4-ROL. In the eye, the STRA6 membrane receptor binds to circulatory RBP4 and internalizes ROL. STRA6 is however not expressed in systemic tissues, where there is high-affinity RBP4 binding and ROL uptake. We tested the hypothesis, that the second retinol-binding protein 4 receptor 2 (Rbpr2) which is highly expressed in systemic tissues of zebrafish and mouse, contains a functional RBP4 binding domain, critical for ROL transport. As for STRA6, modeling and docking studies confirmed three conserved RBP4 binding residues in zebrafish Rbpr2. In cell culture studies, disruption of the RBP4 binding residues on Rbpr2 almost completely abolished uptake of exogenous vitamin A. CRISPR generated rbpr2-RBP4 domain zebrafish mutants showed microphthalmia, shorter photoreceptor outer segments, and decreased opsins, that were attributed to impaired ocular retinoid content. Injection of WT-Rbpr2 mRNA into rbpr2 mutant or all-trans retinoic acid treatments rescued the mutant eye phenotypes. In conclusion, zebrafish Rbpr2 contains a putative extracellular RBP4-ROL ligand-binding domain, critical for yolk vitamin A transport to the eye for ocular retinoid production and homeostasis, for photoreceptor cell survival.

scholarly journals A Functional Binding Domain in the Rbpr2 Receptor Is Required for Vitamin A Transport, Ocular Retinoid Homeostasis, and Photoreceptor Cell Survival in Zebrafish

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1099
Author(s):  
Ashish K. Solanki ◽  
Altaf A. Kondkar ◽  
Joseph Fogerty ◽  
Yanhui Su ◽  
Seok-Hyung Kim ◽  
...  
Keyword(s):  
Vitamin A ◽  
Cell Survival ◽  
Photoreceptor Cell ◽  
Binding Protein ◽  
Binding Domain ◽  
Human Vision ◽  
Retinol Binding Protein ◽  
Dietary Vitamin ◽  
Binding Residues ◽  
Vitamin A Transport

Dietary vitamin A/all-trans retinol/ROL plays a critical role in human vision. ROL circulates bound to the plasma retinol-binding protein (RBP4) as RBP4-ROL. In the eye, the STRA6 membrane receptor binds to circulatory RBP4 and internalizes ROL. STRA6 is, however, not expressed in systemic tissues, where there is high affinity RBP4 binding and ROL uptake. We tested the hypothesis that the second retinol binding protein 4 receptor 2 (Rbpr2), which is highly expressed in systemic tissues of zebrafish and mouse, contains a functional RBP4 binding domain, critical for ROL transport. As for STRA6, modeling and docking studies confirmed three conserved RBP4 binding residues in zebrafish Rbpr2. In cell culture studies, disruption of the RBP4 binding residues on Rbpr2 almost completely abolished uptake of exogenous vitamin A. CRISPR-generated rbpr2-RBP4 domain zebrafish mutants showed microphthalmia, shorter photoreceptor outer segments, and decreased opsins, which were attributed to impaired ocular retinoid content. Injection of WT-Rbpr2 mRNA into rbpr2 mutant or all-trans retinoic acid treatment rescued the mutant eye phenotypes. In conclusion, zebrafish Rbpr2 contains a putative extracellular RBP4-ROL ligand-binding domain, critical for yolk vitamin A transport to the eye for ocular retinoid production and homeostasis, for photoreceptor cell survival.

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