| 2.A.65 The Bilirubin Transporter (BRT) Family
The BRT family consists of a single protein, the 'bilitranslocase', a hepatic plasma membrane bilirubin transporter involved in the uptake of bilirubin and other organic anions from the blood into liver cells. The protein contains a bilirubin-binding motif, and it binds bilirubin with exceptionally high affinity (2 nM) (Battiston et al., 1998). This motif is also present in α-phycocyanines, biliproteins present in cyanobacteria. BRT also takes up a variety of cholephilic organic anions such as bromosulphophthalein (BSP), the related phthalein thymol blue, the antibiotic, rifamycin, and the vitamin precursor, nicotinic acid (Župerl et al., 2011). Sulfobromophthalein has been shown to be transported electrogenically (Passamonti et al., 2005). The carrier may exist in two interchangeable forms with high (5 μM for BSP) and low (37 μM for BSP) affinities for its substrates. Phenylmethylsulfonyl fluoride inactivates bilitranslocase (Passamonti et al., 1999).
The bilitranslocase exhibits 3-5 peaks of hydrophobicity, each of a length sufficient to pass through the membrane as an α-helix. The first is a 'certain' transmembrane α-helix spanner (TMS) according to the TopPred program, and the amphipathicity of two more have been reported (Choudhury et al. 2013). The topology is therefore uncertain. The rat bilitranslocase shows sequence similarity with no other protein in the NCBI database as of July 2012, not even in mice or humans. However, it may be more wide spread (Petrussa et al., 2010). One of the putative TMSs has been shown to be α-helical (Perdih et al., 2012). Rat liver shows increased expression of bilitranslocase from animals with obstructive cholestasis (Brandoni et al., 2010). Bilitranslocase mediates the uptake of some flavenoids such as cyanidin-3-glucoside which may have a protective effect against oxidative stress (Ziberna et al., 2012).
The presumed transport reaction catalyzed by bilitranslocase is:
Bilirubin (out) + nNa+ (out) → bilirubin (in) + nNa+ (in)
|
| References: |
Battiston, L., S. Passamonti, A. Macagno, and G.L. Sottocasa. (1998). The bilirubin-binding motif of bilitranslocase and its relation to conserved motifs in ancient biliproteins. Biochem. Biophys. Res. Commun. 247: 687-692.
|
Brandoni, A., G. Di Giusto, R. Franca, S. Passamonti, and A.M. Torres. (2010). Expression of kidney and liver bilitranslocase in response to acute biliary obstruction. Nephron Physiol 114: p35-40.
|
Passamonti, S., L. Battiston, and G.L. Sottocasa. (1999). On the mechanism of bilitranslocase transport inactivation by phenylmethylsulphonyl fluoride. Mol. Membr. Biol. 16: 167-172.
|
Passamonti, S., M. Terdoslavich, A. Margon, A. Cocolo, N. Medic, F. Micali, G. Decorti, and M. Franko. (2005). Uptake of bilirubin into HepG2 cells assayed by thermal lens spectroscopy. Function of bilitranslocase. FEBS J. 272: 5522-5535.
|
Perdih, A., A. Roy Choudhury, S. Zuperl, E. Sikorska, I. Zhukov, T. Solmajer, and M. Novič. (2012). Structural analysis of a Peptide fragment of transmembrane transporter protein bilitranslocase. PLoS One 7: e38967.
|
Petrussa, E., E. Braidot, M. Zancani, C. Peresson, A. Bertolini, S. Patui, V. Casolo, S. Passamonti, F. Macrì, and A. Vianello. (2010). Immunohistochemical localisation of a putative flavonoid transporter in grape berries. Methods Mol Biol 643: 291-306.
|
Roy Choudhury, A., A. Perdih, S. Zuperl, E. Sikorska, T. Solmajer, S. Jurga, I. Zhukov, and M. Novič. (2013). Structural elucidation of transmembrane transporter protein bilitranslocase: conformational analysis of the second transmembrane region TM2 by molecular dynamics and NMR spectroscopy. Biochim. Biophys. Acta. 1828: 2609-2619.
|
Roy Choudhury, A., E. Sikorska, J. van den Boom, P. Bayer, &.#.3.2.1.;. Popenda, K. Szutkowski, S. Jurga, M. Bonomi, A. Sali, I. Zhukov, S. Passamonti, and M. Novič. (2015). Structural Model of the Bilitranslocase Transmembrane Domain Supported by NMR and FRET Data. PLoS One 10: e0135455.
|
Szutkowski, K., E. Sikorska, I. Bakanovych, A.R. Choudhury, A. Perdih, S. Jurga, M. Novič, and I. Zhukov. (2019). Structural Analysis and Dynamic Processes of the Transmembrane Segment Inside Different Micellar Environments-Implications for the TM4 Fragment of the Bilitranslocase Protein. Int J Mol Sci 20:.
|
Ziberna, L., F. Tramer, S. Moze, U. Vrhovsek, F. Mattivi, and S. Passamonti. (2012). Transport and bioactivity of cyanidin 3-glucoside into the vascular endothelium. Free Radic Biol Med 52: 1750-1759.
|
Župerl, &.#.3.5.2.;., S. Fornasaro, M. Novič, and S. Passamonti. (2011). Experimental determination and prediction of bilitranslocase transport activity. Anal Chim Acta 705: 322-333.
|
| Examples: |
| TC# | Name | Organismal Type | Example |
| 2.A.65.1.1 | The bilirubin transporter (bilitranslocase; BLT) of 340 aas and 3 or 4 TMSs. A structural model has been proposed (Roy Choudhury et al. 2015). Strangely, no homologues are present in the NCBI protein database as of September, 2019, even from another mammal. A possible distant homologue is a hypothetical protein AUH14_01145 of 333 aas and 1 - 3 TMSs, the Candidatus Rokubacteria bacterium 13_2_20CM_69_15_1] (ACCESSION # OLB08456). Structural analyses of TMSs in different micellar environments have been published (Szutkowski et al. 2019). | Animals | Bilitranslocase of Rattus norvegicus |
| |