Transmembrane binding domains TMDs

Figure 9.8 MDRl gene product P-glycoprotein. The protein has 12 membrane spanning sequences both ends of the protein are localized at the interior surface of the membrane. NBD, nucleotide-binding domain TMD, transmembrane domain (from Ref. [37]).

ABC Transporters. Figure 1 Structure of ABCB 1, ABCC1, and ABCG2 (NBF nucleotide binding fold TMD transmembrane domaine. Modified according to www.iwaki-kk.co.jp/bio/specialedition/se02.htm). 

The ABC transporters are products of one of the largest gene superfamilies. Each consists of two cytoplasmic nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs). The NBDs are highly conserved across the ABC family and contain motifs typical of ATP-binding sites, whereas the TMD structures vary, probably because they are adapted to the wide variety of substrates. In eukaryotes the C-terminal of each NBD is linked to a TMD. In some cases the functional unit is (NBD-TMD)2 and, in others, the first TMD is covalently linked to the second NBD. 

All ABC transporters contain four essential modules, two nucleotide binding domains (N BDs) and two transmembrane domains (TMDs). These four modules can be encoded by four separate genes or fused pairwise in all possible combinations [35, 37]. Bacterial MDRs are usually homo- or heterodimers in which one NBD is fused to one TMD. This is the case for the most well-studied bacterial ABC MDRs, LmrA [38] and LmrCD [39], both from Lactococcus lactis. 

Transporters are integral membrane proteins that typically have 12 transmembrane domains (TMDs), althongh some have 6, 8, 10, 11, 13 or even 17 TMDs. The TMDs are folded in a-heUcal stractures within the membrane and linked at both sides by amino acid seqnences floating in the internal or external cell environment. The amino acids in the external loop domains are freqnently A/-glycosylated, while those of the intracellnlar loops of SLC, ABC and MATE proteins bear phosphorylation sites the ABCs also have one or two ATP-binding domains. The 3D stmcture of TMDs is a crown shape, and they look like a channel allowing communication between the two fluid spaces separated by the lipid bilayer (Figure 34.3). Many SLC and MATE transporters have 300-800 amino acid residues and a molecular... 

The breast cancer resistance protein (BCRP) belongs to the G-branch of the ABC-transporter family (ABCG2). In contrast to most other ABC-proteins, BCRP consists of only one transmembrane domain (TDM) with one nucleotide binding fold (NBF) at its C-terminus. Because of this structural characteristic BCRP as well as other ABC-transporters with only one TMD are termed half transporters. To achieve functional activity these transporters have to form hetero- or homodimers. BCRP is involved in the multidrug resistance of certain tumors and transports endogenous compounds like cholesterol and steroid hormones. 

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