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ABC Transporters Family

ABC (ATP‑binding cassette) proteins form one of the largest and most diverse protein superfamilies, whose members can be found in all eukaryotic and prokaryotic organisms studied to date. The most of ABC proteins are transporters that translocate allocrites across biological membranes. Almost half of the 48 human ABC transporter proteins are thought to facilitate the ATP-dependent translocation of lipids or lipid-related compounds. Such substrates include cholesterol, plant sterols, phospholipids, bile acids and sphingolipids. Mutations in a substantial number of the 48 human ABC transporters have been related to human disease.

The ABCs of lipid transport

ABC transporters are transmembrane proteins that utilize the hydrolysis of ATP to facilitate the movement of a wide variety of substrates across membrane bilayers. There are more than 250 members in the ABC superfamily that can be thought of as importers or exporters. Importers are typically associated with the uptake of hydrophilic nutrients, such as peptides, sugars and ions, into the cell, and are common in bacteria and absent from eukaryotes. Both eukaryotes and prokaryotes possess ABC transporters that function to export substrates out of the cytosol, either into an organelle or across the plasma membrane and out of the cell.

Proteins are classified as ABC transporters based on the organization of their ATP-binding cassette, a region that spans 180 amino acids, and contains three highly conserved motifs: the Walker A/P-loop (12 amino acids), the Walker B motif (5 amino acids) and a signature motif/C-loop (5 amino acids). Functional ABC transporters contain two transmembrane domains (TMD), each commonly thought to consist of six transmembrane a-helices and two ABCs (Figure 1). ABC transporters can be further divided into either ‘half’ or ‘full’ transporters. Half-transporters, in which the polypeptide chain encodes only one TMD and one ABC, are thought to homo- or hetero-dimerize to form a functional transporter. In full transporters, the two TMD and two ABCs are encoded by a single polypeptide, where the two ABCs interact and hydrolyze ATP, thereby generating energy for substrate transport.

ABC Transporters Family Figure 1. The architecture of ABC transporters. (a) Domain arrangement of ABC transporters. (b) Schematic of a single NBD.

Cellular location

Twenty of the 48 human ABC transporters are thought to transport lipids or lipid-related compounds (Figure 2). Approximately half of them are localized to intracellular organelles such as peroxisomes (ABCD1–3), lysosomes (ABCA2, ABCA5), lamellar bodies (ABCA12, ABCA3), and endosomes (ABCG1, ABCG4). Despite contrasting reports about whether ABCG1 and/or ABCG4 are present at the plasma membrane, it should be noted that loss of ABCG1 results in many specific cell-intrinsic defects, suggesting that maintenance of intracellular lipid distribution by ABCG1 is critical. This widespread intracellular localization of different ABC transporters suggests that the precise distribution of lipids within membranes is essential not only for membrane structure but also for cell and organelle function. For example, loss of ABCD1 function results in the accumulation of saturated very long chain fatty acids due to impaired import into the peroxisome where they would normally undergo b-oxidation. Moreover, functional loss of ABCA3 or ABCA12 from lamellar bodies results in the impaired import of lipids into this organelle, leading to defects in pulmonary surfactant secretion (ABCA3) or maintenance of skin barrier function (ABCA12).

ABC Transporters Family Figure 2. Localization of ABC lipid transporters.

Lipid transporters and disease

There are 48 ABC transporters in humans that can be subdivided by phylogenetic analysis into seven distinct subfamilies A-G. Mammalian ABC transporters are involved in the cellular export of several groups of molecules, including cholesterol and sterols, lipids, bile acid, iron, retinoic acid derivatives, nucleosides, and peptides. The essential nature of these functions is highlighted by the fact that defects in the associated transporters have been observed in many genetic conditions, including Tangier (ABCA1) and Stargardt (ABCA4) disease, immune deficiency and cancer (ABCB2/3; TAP transporter), cystic fibrosis (cystic fibrosis transmembrane conductance regulator [CFTR]; ABCC7), and adrenoleukodystrophy (ABCD1), etc.

Another prominent group of human ABC transporters is found in the placenta, liver and blood brain barrier where they are involved in the detoxification of hydrophobic organic molecules. The group includes P-glycoprotein (ABCB1), the MRP (ABCC1) and ABCG2. These transporters, when found highly expressed in the plasma membrane of tumor cells, can result in the failure of chemotherapy by protecting the cancer cells from the cytotoxic drugs used to fight the disease. Much effort has been spent on identifying selective inhibitors for these MDR transporters and while many compounds have been identified that inhibit P-glycoprotein function in, no broadly applicable inhibitor is in use as of yet, due to significant side effects of the compounds.

Table 1. ABC lipid transporters mutated in human disease

ABC Transporters Family

Conclusions

Membrane distribution of intracellular lipids is crucial for cellular function and signaling. In fact, mutations in many of these ABC lipid transporters results in human diseases, such as Tangier disease, sitosterolemia and familial intrahepatic cholestasis. The ABC transporter superfamily is a well-characterized protein family, but the substrates and roles of a number of these proteins in human disease are unknown. Substrate specificity has mostly been inferred from the identification of metabolites/compounds that accumulate in humans with specific diseases and in knockout mouse models. In the case of ABC proteins that transport drugs or small molecules, direct substrate transport can be demonstrated by the well-established in vitro vesicle-transport assay. However, for ABC lipid transporters, those transport assays are inherently more difficult because of the hydrophobic nature of the lipid substrate. Identification of the molecular mechanism of lipid transport/movement by ABC transporters will require the development of novel assays to overcome the problems associated with the insolubility of the substrates.

References:

  1. Vasiliou V, et al. Human ATP-binding cassette (ABC) transporter family. Hum Genomics, 2009, 3(3):281.
  2. Wilkens S. Structure and mechanism of ABC transporters. F1000prime Rep, 2014, 7:14.
  3. Zolnerciks J K, et al. Structure of ABC transporters. Essays in Biochemistry, 2011, 50(1):43.
  4. Tarling E J. Role of ABC transporters in lipid transport and human disease. Trends in Endocrinology & Metabolism Tem, 2013, 24(7):342-350.
  5. Tsybovsky Y, et al. The ATP-binding cassette transporter ABCA4: structural and functional properties and role in retinal disease. Oxygen Transport to Tissue XXXIII, 2010, 703:105-125.
  6. Nicolaou M, et al. Canalicular ABC transporters and liver disease. Journal of Pathology, 2012, 226(2):300.
  7. Locher K P. Mechanistic diversity in ATP-binding cassette (ABC) transporters. Nature Structural & Molecular Biology, 2016, 23(6):487.
For research use only. Not intended for any clinical use.

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