Abstract
Vitamin A and its derivatives (retinoids) play diverse and crucial functions from embryogenesis to adulthood and are used as therapeutic agents in human medicine for eye and skin diseases, infections and cancer. Plasma retinol binding protein (RBP) is the principal and specific vitamin A carrier in the blood and binds vitamin A at 1∶1 ratio. STRA6 is the high-affinity membrane receptor for RBP and mediates cellular vitamin A uptake. STRA6 null mice have severely depleted vitamin A reserves for vision and consequently have vision loss, even under vitamin A sufficient conditions. STRA6 null humans have a wide range of severe pathological phenotypes in many organs including the eye, brain, heart and lung. Known membrane transport mechanisms involve transmembrane pores that regulate the transport of the substrate (e.g., the gating of ion channels). STRA6 represents a new type of membrane receptor. How this receptor interacts with its transport substrate vitamin A and the functions of its nine transmembrane domains are still completely unknown. These questions are critical to understanding the molecular basis of STRA6′s activities and its regulation. We employ acute chemical modification to introduce chemical side chains to STRA6 in a site-specific manner. We found that modifications with specific chemicals at specific positions in or near the transmembrane domains of this receptor can almost completely suppress its vitamin A transport activity. These experiments provide the first evidence for the existence of a transmembrane pore, analogous to the pore of ion channels, for this new type of cell-surface receptor.
Highlights
Vitamin A is a multifunctional chemical essential for human life
We studied the effect of chemical modification on STRA6-mediated vitamin A uptake using both 3H-retinol-based vitamin A uptake assay and HPLC-based analysis of retinyl ester formation as a result of the coupling of STRA6-mediated vitamin A uptake to lecithin retinol acyltransferase (LRAT) [32,37,48] (Figure 3). 3H-retinol/retinol-binding protein (RBP) can reveal both RBP’s binding to STRA6 and STRA69s coupling to LRAT, because 3H-retinol associated with STRA6 without LRAT largely reflects 3H-retinol/RBP bound to STRA6 [49]
The RBP receptor is a new type of cell-surface receptor, and the structural basis of this receptor’s substrate transport is unknown due to its recent discovery and the technical challenges in studying it
Summary
Vitamin A is a multifunctional chemical essential for human life. In addition to its function as the light sensor in vision [1,2,3,4,5,6], vitamin A plays critical roles in almost all human organs and regulates cell growth and differentiation from embryogenesis to adulthood [7,8]. The crystal structures of RBP and its complex with transthyretin have been determined [27,28]. It was first proposed in the 1970s that a cell-surface receptor mediates vitamin A uptake from RBP [29,30,31]. This receptor has been identified as a multitransmembrane domain protein STRA6 [32]. STRA6 binds to RBP with high affinity and mediates cellular uptake of vitamin A [32]
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