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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. Vitamin A transporters play important roles in visual function and serve as membrane receptors for dietary Vitamin A uptake, storage, and transport to the eye (Martin Ask et al. 2021).

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, transporting 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. STRA6 is essential for induction of vascular smooth muscle lineages in human embryonic cardiac outflow tract development (Zhou et al. 2023).

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. 

Vitamin A has diverse biological functions and has been used to treat human diseases including vision diseases, skin diseases, and cancer. Both insufficient and excessive vitamin A uptake are detrimental. STRA6 can mediate both cellular vitamin A influx and efflux. Zhong et al. 2020 purified and identified STRA6-associated proteins and found that the major STRA6-associated protein is calmodulin, consistent with the cryogenic electron microscopy (cryo-EM) study of zebrafish STRA6 associated with calmodulin. They showed that increased calcium/calmodulin promotes cellular vitamin A efflux and suppresses vitamin A influx through STRA6.  Also, calmodulin enhances the binding of apo-RBP to STRA6, and this enhancement is much more pronounced for apo-RBP than holo-RBP. Thus, calmodulin regulates STRA6's vitamin A influx vs efflux activity by modulating its preferential interaction with apo-RBP or holo-RBP (Zhong et al. 2020).

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
Alapatt, P., F. Guo, S.M. Komanetsky, S. Wang, J. Cai, A. Sargsyan, E. Rodríguez Díaz, B.T. Bacon, P. Aryal, and T.E. Graham. (2013). Liver retinol transporter and receptor for serum retinol-binding protein (RBP4). J. Biol. Chem. 288: 1250-1265. 23105095
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
Martin Ask, N., M. Leung, R. Radhakrishnan, and G.P. Lobo. (2021). Vitamin A Transporters in Visual Function: A Mini Review on Membrane Receptors for Dietary Vitamin A Uptake, Storage, and Transport to the Eye. Nutrients 13:. 34836244
Radhakrishnan, R., M. Leung, A.K. Solanki, and G.P. Lobo. (2023). Mapping of the extracellular RBP4 ligand binding domain on the RBPR2 receptor for Vitamin A transport. Front Cell Dev Biol 11: 1105657. 36910150
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
Xiao, Q., L. Wang, S. Supekar, T. Shen, H. Liu, F. Ye, J. Huang, H. Fan, Z. Wei, and C. Zhang. (2020). Structure of human steroid 5α-reductase 2 with the anti-androgen drug finasteride. Nat Commun 11: 5430. 33110062
Zhong, M., R. Kawaguchi, B. Costabile, Y. Tang, J. Hu, G. Cheng, M. Kassai, B. Ribalet, F. Mancia, D. Bok, and H. Sun. (2020). Regulatory mechanism for the transmembrane receptor that mediates bidirectional vitamin A transport. Proc. Natl. Acad. Sci. USA 117: 9857-9864. 32300017
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
Zhou, C., T. Häneke, E. Rohner, J. Sohlmér, P. Kameneva, A. Artemov, I. Adameyko, and M. Sahara. (2023). STRA6 is essential for induction of vascular smooth muscle lineages in human embryonic cardiac outflow tract development. Cardiovasc Res. [Epub: Ahead of Print] 36635482