Transmembrane protein series four: ATP-binding cassette transporters

What is ATP-binding cassette transporter?

Transmembrane proteins span the lipid bilayer. According to the number of transmembrane times, it can be divided into one transmembrane protein or multiple transmembrane proteins. Many naturally occurring transmembrane proteins act as channels for specific substances to pass through the biofilm. Some transmembrane proteins can receive or transmit cellular signals. Transmembrane proteins also play an important role in molecular transport.

ATP-binding cassette (ABC) transporter, also known as ABC protein, is a transmembrane protein involved in molecular transport.

ATP-binding cassette transporters are the largest known transmembrane protein superfamily. ABC proteins bind and hydrolyze ATP and use energy to drive various molecules across the plasma membrane as well as the endoplasmic reticulum (ER), peroxisome and mitochondrial inner membrane. It is involved in the transport of specific molecules on the lipid membrane and the resistance in all organisms.

How does ATP-binding cassette transporter work?

ABC transporters are involved in a variety of important transport processes in organisms, and their transport functions require the participation of both nucleotide binding domains(NBDs) and transmembrane domains(TMDs). The transport function of the ABC transporter family is divided into two modes of transport: import mechanism and export mechanism. As shown in Figure 1, the transport function of ABC transporters is a circular process. Taking the importer as an example, at the beginning, ABC transporter is in the inward-facing conformation. At this time, two NBDs remain open driven by the transmembrane domain. When substrate-binding proteins(SBPs) deliver a substrate to the TMDs, the NBDs bind and hydrolyze ATP, accompanied by the change of TMDs conformation, at which time the ABC transporter becomes outward-facing conformation. The subsequent hydrolysis of ATP leads to substrate uptake across the lipid bilayer and phosphate release makes the transporter revert to the inward-facing conformation.

Figure 1. Mechanism of ABC importers ^[1]

ATP-binding cassette (ABC) transporters and disease

ABC gene mutations are associated with the development of certain diseases. These diseases include adrenal white matter dystrophy, cystic fibrosis, retinal degeneration, hypercholesterolemia and cholestasis, neurological diseases, anemia and drug reactions.

Some common single nucleotide polymorphisms in ABCA1 also affect blood lipid levels, atherogenesis, and the severity of coronary heart disease.

ATP-binding cassette (ABC) transporters and drug resistance

MDR refers to the phenomenon that tumor cells have cross-resistance to multiple chemotherapy drugs. This condition is mainly caused by the efflux of cytotoxic drugs mediated by ATP-binding cassette transporter. In the chemotherapy of liver cancer, pancreatic cancer and other tumors, ATP-binding cassette transporter-mediated MDR seriously restricts the efficacy and prognosis of chemotherapy.

ATP-binding cassette (ABC) transporters inhibitors

Evading MDR can inhibit MDR1 synthesis and its activity at the mRNA level, or compete for MDR1 binding sites. In addition, the reversal methods of MDR include immunotherapy reversal, gene reversal, reversal of somatostatin and its analogues, and reversal of Chinese herbal medicine. More information about ABC, you can have a look at this article: A transport machine -- ATP-binding cassette.

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