TCDB is operated by the Saier Lab Bioinformatics Group

2.A.90 The Vitamin A Receptor/Transporter (STRA6) Family

The bovine STRA6 (stimulated by retinoic acid-6) protein (668 aas) is a multispan integral membrane protein with 11-12 TMSs. Mammals contain multiple paralogues or partial paralogues showing regions of sequence similarity. These can be short (~200 aas) or long (1708 aas, EAW58841; the KIAA1528, isoform CRA_b of Homo sapiens; sequence similarity between residues 17-314 with residues 311-668 of STRA6). KIAA1528 has 5-6 putative N-terminal TMSs (residues 1-250) followed by an ~1500 residue long hydrophilic C-terminal region (Wolf 2007). These homologues do not show sequence similarity with any other proteins in TCDB.

The bovine STRA6 homologue has been reported to be a receptor for retinol binding protein (RBP). It binds RBP with high affinity and apparently extracts the vitamin A from the RBP-vitamin A complex and transports it into the cell (Kawaguchi et al., 2007). It is widely expressed in embryonic tissues and in adult organs. Homologues are found only in animals.

It has been suggested that STRA6 is a transmembrane pore which transports vitamin A bidirectionally between extra- and intracellular retinoid binding proteins and that vitamin A accumulation in cells is driven by coupling of transport with vitamin A esterification (Kelly and von Lintig 2015). Thus, it is not clear what the mechanisms of transport and energy coupling are. 

Loss-of-function studies in zebrafish and mouse models have unraveled the critical importance of STRA6 for vitamin A homeostasis of peripheral tissues. Impairment in vitamin A transport and uptake homeostasis are associated with diseases including type 2 diabetes and a microphthalmic syndrome known as Matthew Wood Syndrome (Kelly and von Lintig 2015).

Retinol-binding protein (RBP) is the sole 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. Chen et al. 2016 presented 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. 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.


The reaction catalyzed (reversibly?) by STRA6 is:

vitamin A (out) → vitamin A (in).




References associated with 2.A.90 family:

and Sun H. (2012). Membrane receptors and transporters involved in the function and transport of vitamin A and its derivatives. Biochim Biophys Acta. 1821(1):99-112. 21704730
Breen, C.J., D.S. Martin, H. Ma, K. McQuaid, R. O''Kennedy, and J.B. Findlay. (2015). Production of functional human vitamin A transporter/RBP receptor (STRA6) for structure determination. PLoS One 10: e0122293. 25816144
Chen, Y., O.B. Clarke, J. Kim, S. Stowe, Y.K. Kim, Z. Assur, M. Cavalier, R. Godoy-Ruiz, D.C. von Alpen, C. Manzini, W.S. Blaner, J. Frank, L. Quadro, D.J. Weber, L. Shapiro, W.A. Hendrickson, and F. Mancia. (2016). Structure of the STRA6 receptor for retinol uptake. Science 353:. 27563101
Kawaguchi, R., J. Yu, J. Honda, J. Hu, J. Whitelegge, P. Ping, P. Wiita, D. Bok, and H. Sun. (2007). A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science 315: 820-825. 17255476
Kawaguchi, R., J. Yu, P. Wiita, M. Ter-Stepanian, and H. Sun. (2008). Mapping the membrane topology and extracellular ligand binding domains of the retinol binding protein receptor. Biochemistry 47: 5387-5395. 18419130
Kawaguchi, R., M. Zhong, M. Kassai, M. Ter-Stepanian, and H. Sun. (2015). Vitamin A Transport Mechanism of the Multitransmembrane Cell-Surface Receptor STRA6. Membranes (Basel) 5: 425-453. 26343735
Kelly, M. and J. von Lintig. (2015). STRA6: role in cellular retinol uptake and efflux. Hepatobiliary Surg Nutr 4: 229-242. 26312242
Wolf, G. (2007). Identification of a membrane receptor for retinol-binding protein functioning in the cellular uptake of retinol. Nutr Rev 65: 385-388. 17867372
Zhong, M., R. Kawaguchi, M. Ter-Stepanian, M. Kassai, and H. Sun. (2013). Vitamin a transport and the transmembrane pore in the cell-surface receptor for plasma retinol binding protein. PLoS One 8: e73838. 24223695