Structure of the STRA6 receptor for retinol uptake

• Published in: Science (American Association for the Advancement of Science) Vol. 353; no. 6302; p. 887
• Main Authors: Chen, Yunting, Clarke, Oliver B., Kim, Jonathan, Stowe, Sean, Kim, Youn-Kyung, Assur, Zahra, Cavalier, Michael, Godoy-Ruiz, Raquel, von Alpen, Desiree C., Manzini, Chiara, Blaner, William S., Frank, Joachim, Quadro, Loredana, Weber, David J., Shapiro, Lawrence, Hendrickson, Wayne A., Mancia, Filippo
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 26.08.2016; The American Association for the Advancement of Science
• Subjects: Animals; Binding; Binding sites; Biological Transport; Calcium; Calcium - chemistry; Calmodulin - chemistry; Calorimetry; Cryoelectron Microscopy; Crystallography; Danio rerio; Electron microscopy; HEK293 Cells; Humans; Mammals; Membrane Proteins - chemistry; Membrane Proteins - genetics; Membrane Transport Proteins - chemistry; Membrane Transport Proteins - genetics; Membranes; Metabolites; Microscopy; Nutrients; Peptides; Protein Binding; Protein Conformation, alpha-Helical; Protein Multimerization; Proteins; Receptors; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; RESEARCH ARTICLE SUMMARY; Retinol-Binding Proteins - chemistry; Retinol-Binding Proteins - genetics; Topology; Translocation; Uptakes; Vitamin A; Vitamin A - metabolism; Vitamins; Zebrafish; Zebrafish Proteins - chemistry; Zebrafish Proteins - genetics
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.aad8266

Vitamin A is an essential nutrient for mammals, and its metabolites affect diverse biological processes. It is carried in the bloodstream as retinol by retinol binding protein (RBP); a protein called STRA6 is implicated in facilitating retinol translocation across the cell membrane. Chen et al. determined the structure of zebrafish STRA6 to a resolution of 3.9 Å by electron microscopy. A lipophilic cleft is a likely binding site for RBP, and an opening in the cleft may allow retinol to diffuse into the membrane. Unexpectedly, the structure also includes bound calcium-modulated protein, but its function remains unclear. Science , this issue p. 887 The structure of a STRA6-calmodulin complex gives insight into how retinol (vitamin A) enters cells. Vitamin A homeostasis is critical to normal cellular function. Retinol-binding protein (RBP) is the sole specific carrier in the bloodstream for hydrophobic retinol, the main form in which vitamin A is transported. The integral membrane receptor STRA6 mediates cellular uptake of vitamin A by recognizing RBP-retinol to trigger release and internalization of retinol. We present the structure of zebrafish STRA6 determined to 3.9-angstrom resolution by single-particle cryo-electron microscopy. STRA6 has one intramembrane and nine transmembrane helices in an intricate dimeric assembly. Unexpectedly, calmodulin is bound tightly to STRA6 in a noncanonical arrangement. Residues involved with RBP binding map to an archlike structure that covers a deep lipophilic cleft. This cleft is open to the membrane, suggesting a possible mode for internalization of retinol through direct diffusion into the lipid bilayer.