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

Ming Zhong, Riki Kawaguchi, Brianna Costabile, Yuyan Tang, Jane Hu, Guo Cheng, Miki Kassai, Bernard Ribalet, Filippo Mancia, Dean Bok, Hui Sun

Proceedings of the National Academy of Sciences of the United States of America 2020 May 05

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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.

Citation

Ming Zhong, Riki Kawaguchi, Brianna Costabile, Yuyan Tang, Jane Hu, Guo Cheng, Miki Kassai, Bernard Ribalet, Filippo Mancia, Dean Bok, Hui Sun. Regulatory mechanism for the transmembrane receptor that mediates bidirectional vitamin A transport. Proceedings of the National Academy of Sciences of the United States of America. 2020 May 05;117(18):9857-9864