13.8:
ABC Transporters: Exporter
ATP-binding cassette or ABC transporters form the largest family of membrane transporters.
These transporters contain two transmembrane domains that span the lipid bilayer and two cytoplasmic nucleotide-binding or ATP-binding domains.
ABC transporters can act as importers as well as exporters of solutes at the cell membrane.
While the exporters are present in both prokaryotes and eukaryotes, importers are only found in prokaryotes and some plants.
Consider an ABC exporter present on a eukaryotic cell membrane.
Initially, the transporter is present in the inward-facing conformation, with the solute-binding site exposed towards the cytosol. When a cytosolic solute binds to the transporter, it increases the affinity of ATP-binding domains towards ATP.
Binding of the ATP molecules to the transporter triggers a change in the protein conformation from inward-facing to outward-facing. This conformational change releases the solute into the extracellular space.
The attached ATP is then hydrolyzed into ADP and inorganic phosphate, prompting the two ATP-binding domains to separate. This reverts the transporter to its initial inward-facing conformation.
13.8:
ABC Transporters: Exporter
ATP-binding cassette or ABC transporter is the largest superfamily of integral membrane proteins. The transporters have transmembrane-binding domains (TMDs) and nucleotide-binding domains (NBDs). The TMDs are specific to their substrates, whereas the NBDs are similar to engines that complete ATP hydrolysis to complete the substrate transport. They can be full transporters consisting of two TMDs and NBDs, half transporters with one TMD and NBD, while some encoded with a single TMD or NBD are single-domain structures.
The eukaryotic ABC transporters can only function as exporters of solute. Except for some plants, bacteria have both ABC importers and exporters.
There are 49 known ABC genes in humans, classified into seven families. The ATP-binding cassette sub-family B member 1 (ABCB1) or P-glycoprotein 1 is responsible for transporting various natural and metabolic toxins out of the cells. However, during its evolution, ABCB1 acquired the ability to transport drugs whose structures are similar to those of endogenous toxins, thus becoming a significant cause of drug resistance. This is a massive concern while treating cancer, as it prevents intracellular accumulation of anti-cancer drugs and reduces treatment efficacy.
In a related example, Plasmodium falciparum, a unicellular eukaryote that causes malaria, is commonly treated with chloroquine. However, over time, it has developed resistance to chloroquine due to mutations in the Plasmodium falciparum multidrug resistance protein 1 (PfMDR1) transporter that helps reduce intracellular drug concentration.
Suggested Reading
- El-Awady, Raafat, Ekram Saleh, Amna Hashim, Nehal Soliman, Alaa Dallah, Azza Elrasheed, and Ghada Elakraa. "The role of eukaryotic and prokaryotic ABC transporter family in failure of chemotherapy." Frontiers in pharmacology 7 (2017): 535.
- Procko, Erik, Megan L. O'Mara, WF Drew Bennett, D. Peter Tieleman, and Rachelle Gaudet. "The mechanism of ABC transporters: general lessons from structural and functional studies of an antigenic peptide transporter." The FASEB Journal 23, no. 5 (2009): 1287-1302.
- Linton, Kenneth J. "Structure and function of ABC transporters." Physiology 22, no. 2 (2007): 122-130.
- Ye, Zixiang, Yifei Lu, and Tao Wu. "The impact of ATP-binding cassette transporters on metabolic diseases." Nutrition & Metabolism 17, no. 1 (2020): 1-14.