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

Abstract

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.

• Authors: Ming Zhong, Riki Kawaguchi, Brianna Costabile, Yuyan Tang, Jane Hu, Guo Cheng, Miki Kassai, Bernard Ribalet, Filippo Mancia, Dean Bok, Hui Sun
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 18 Pg. 9857-9864 (05 05 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 32300017 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Apoproteins
• Calmodulin
• Membrane Proteins
• Receptors, Cell Surface
• Retinol-Binding Proteins, Plasma
• STRA6 protein, human
• Vitamin A
• Calcium

Topics

• Animals
• Apoproteins (genetics, metabolism)
• Biological Transport (genetics)
• Calcium (metabolism)
• Calmodulin (genetics)
• Cattle
• Cell Line
• Chromatography, High Pressure Liquid
• Cryoelectron Microscopy
• Humans
• Membrane Proteins (genetics, metabolism)
• Protein Binding (genetics)
• Receptors, Cell Surface (genetics)
• Retinol-Binding Proteins, Plasma (genetics, metabolism)
• Vitamin A (genetics, metabolism)
• Zebrafish (genetics)