ABC Transporters

Transporters belonging to the ATP-Binding Cassette (or ABC) family of proteins have the ability to transport substrates across cellular membranes against a concentration gradient using the energy of ATP hydrolysis. They are so called because of their distinctive ATP-binding domains, which contain highly conserved sequences, Walker A and Walker B and an additional ABC "signature" sequence. ABC proteins constitute the largest subclass of transmembrane proteins and are expressed ubiquitously in all living organisms, including bacteria, plants, and animals. Collectively, they are responsible for transporting a multitude of diverse substrates including sugars, ions, lipids and phospholipids, peptides, bile acids, sterols, pigments, and xeno-biotics across membranes, thus affecting the distribution of molecules at subcellular, cellular, and tissue levels. There are many different ABC transporters. The mammalian ones have now been classified into subfamilies, termed ABC A through ABCG (http://www.humanabc.org/). In this scheme, BCRP is named as ABCG2. The reader is directed to http://www.ncbi.nlm.nih.gov/books/bookres. fcgi/mono_001/mono_001.pdf and http://arjournals. annualreviews.org/doi/pdf/10.1146/annurev.biochem. 71.102301.093055 for two comprehensive reviews on ABC transporters.

Structural Organization of ABC Transporters

Many of the ABC transporters are constructed as a tandem repeat of a basic unit containing two domains: an N-terminal transmembrane domain (TD) of 6 to 11 a-helices that provide substrate specificity to the protein, and a C-terminal nucleotide-binding domain (NBD) located in the cytoplasm that binds and cleaves ATP in order to generate the energy for substrate transport. Binding and subsequent hydrolysis of ATP result in a conformational change that causes the substrate to be translocated across the membrane. This general structure is typified by the mammalian mul-tidrug transporter, P-glycoprotein, otherwise named ABCB1 (Figure 1). Some ABC transporters including the Multidrug Resistance-associated Protein, MRP1 (ABCC1), have an additional N-terminal TD. However others contain only one NBD and one TD. This "half transporter" structure is

Figure 1 Putative membrane topology of the three main multidrug transporters. BCRP consists of one transmembrane domain (TD) and one nucleotide binding domain (NBD) and is termed a half-transporter. P-glycoprotein, like many ABC proteins, is a full transporter with a TDj-NBDj-TD2-NBD2 structure. Several of the MRP family members, including MRP1, have an additional N-terminal TD linked to the P-gp-like core by a linker region (L0). Note that the TD and NBD in BCRP are in reverse orientation to those of the other two ABC proteins. (N and C refer to the N and C termini of the transporter, respectively.) (see color insert)

Figure 1 Putative membrane topology of the three main multidrug transporters. BCRP consists of one transmembrane domain (TD) and one nucleotide binding domain (NBD) and is termed a half-transporter. P-glycoprotein, like many ABC proteins, is a full transporter with a TDj-NBDj-TD2-NBD2 structure. Several of the MRP family members, including MRP1, have an additional N-terminal TD linked to the P-gp-like core by a linker region (L0). Note that the TD and NBD in BCRP are in reverse orientation to those of the other two ABC proteins. (N and C refer to the N and C termini of the transporter, respectively.) (see color insert)

exemplified by members of several ABC subfamilies including the ABCG subfamily of which BCRP is a member. In addition, members of this subfamily have their TD and NBD in reverse orientation (see Figure 1); hence, BCRP is referred to as a "reverse" half-transporter. Half transporters have to dimerize with a partner protein (either with itself to form a homodimer or with another protein to form a het-erodimer) in order to be functional. Currently, the bulk of the evidence points to BCRP being a homodimer. Interestingly however, BCRP shows closest homology with the white, brown, and scarlet proteins that heterodimerize (white/brown and white/scarlet) to transport pigment precursors (guanine and tryptophan) in the Drosophila eye.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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