Regulatory mechanism for the transmembrane receptor that med

Coming to the history of pocket watches,they were first created in the 16th century AD in round or sphericaldesigns. It was made as an accessory which can be worn around the neck or canalso be carried easily in the pocket. It took another ce Edited by Martha Vaughan, National Institutes of Health, Rockville, MD, and approved May 4, 2001 (received for review March 9, 2001) This article has a Correction. Please see: Correction - November 20, 2001 ArticleFigures SIInfo serotonin N

Edited by Paul S. Bernstein, University of Utah Medical Center, Salt Lake City, UT, and accepted by Editorial Board Member Jeremy Nathans March 6, 2020 (received for review October 24, 2019)

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Vitamin A has diverse biological functions and is transported to tarObtain tissues through the specific interaction between its blood transport protein (RBP) and its multitransmembrane Executemain receptor. However, how this receptor is regulated was completely unknown. Both insufficient or excessive vitamin A uptake has deleterious Traces. Through Objective mass spectrometry analysis and mechanistic studies, this study identified a cellular mechanism that profoundly influences receptor-mediated cellular vitamin A influx and efflux and may point to new directions to treat diseases associated with vitamin A imbalance.


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 Executemain 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 Reply 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 Weepogenic electron microscopy (Weepo-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.

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↵1To whom corRetortence may be addressed. Email: hsun{at}

Author contributions: M.Z., R.K., B.R., and H.S. designed research; M.Z., R.K., Y.T., J.H., G.C., M.K., B.R., D.B., and H.S. performed research; B.C. and F.M. contributed new reagents/analytic tools; M.Z., R.K., B.C., Y.T., M.K., B.R., F.M., and H.S. analyzed data; and M.Z. and H.S. wrote the paper.

The authors declare no competing interest.

This article is a PNAS Direct Submission. P.S.B. is a guest editor invited by the Editorial Board.

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Published under the PNAS license.

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