Figure 2

Comparison of sequence proportions and functional sensitive features of primary and secondary TH transporters. Sequence scheme of TH transporters expressed at the blood-brain barrier (BBB) is aligned according to the sequences of common 12 transmembrane spanners (pale grey boxes). Sequence lengths, proportions and known sensitive features of transport differ between the three TH transporter families (MCT, OATP, and LAT). The xCT sequences are very homologous to LATs and are therefore added. The human MCT8 possesses a very large N-terminal tail at the intracellular portion. Intra- and extracellularly conserved cysteines are marked in yellow bars. N-glycosylation sites of the OATP family are conserved at large extracellular loops EL2 and EL5 (magenta bars). The proven disulfide bridge formed by the LAT and xCT family to the escort protein 4F2hc are conserved in the EL2 (C165-LAT1_human [49] or C158-xCT_human [50] marked by red dot * at yellow bar). Sensitive positions for TH transport identified by mutations are highlighted: MCT8_human: R445A(# blue bar, TMH8 [26]) and D498A (& red bar, TMH10 [26]), the sensitive arginine and aspartate are conserved at the MCT8 and MCT10 group; Oatp1c1_rat: W277A and W278A (§ green bars, TMH6 [27]), G400A and G410A (■ and ▼green bars, TMH8 [30]), R601A (// blue bar, TMH11 [27]); OATP1A2_human: I13T (◊ N-terminal tail [63]), R168C (▲ blue bar, TMH4 [58]), E172D (◊ red bar, TMH4 [63]). The isoleucine at position 13 (green bar, N-terminal tail) is only conserved at the OATP1A2 group, while the sensitive tryptophan (green bars), arginines (blue bars) and glutamate (red bar) are conserved within the OATP family. At the human xCT may lie close to the substrate binding site H110 (+ blue bar [21]) and T112 (○ green bar [21]) in IL1 and the C327 (~ yellow bar [62]) at TMH8. The accession numbers of these proteins are NM_006517.3 (MCT8_human), NM_009197.2 (MCT8_mouse), NM_147216.1 (MCT8_rat), NM_018593.4 (MCT10_human), NM_001114332.1 (MCT10_mouse), Q91Y77 (MCT10_rat), NM_017435.4 (OATP1C1_human), NM_021471.2 (OATP1C1_mouse), NM_053441.1 (OATP1C1_rat), NM_134431.3 (OATP1A2_human), NM_174654.2 (OATP1A2_bovine), AF205071.1 (OATP1A4_human), NM_030687.1 (OATP1A4_mouse), NM_131906.1 (OATP1A4_rat), BC039692.2 (LAT1_human), BC026131.1 (LAT1_mouse), CH473972.1 (LAT1_rat), NM_001082120.1 (LAT1_rabbit), BC052250.1 (LAT2_human), BC059004.1 (LAT2_mouse), NM_053442.1 (LAT2_rat), NM_001082682.1 (LAT2_rabbit), NM_014331.3 (xCT_human), NM_011990.2 (xCT_mouse), NM_001107673.2 (xCT_rat).