ATP-binding cassette

ATP-binding cassette (ABC) transporters are a large family of proteins that play a crucial role in the cellular transport of molecules across extracellular and intracellular membranes. These proteins utilize the energy derived from the hydrolysis of ATP to translocate a wide variety of substrates, including ions, lipids, sterols, peptides, proteins, and polysaccharides, across cell membranes. Due to their essential functions in transporting nutrients, metabolites, and waste products, ABC transporters are critical for the physiology of living organisms and are implicated in various diseases, including cancer, cystic fibrosis, and drug resistance in pathogens.

Structure and Mechanism

ABC transporters are characterized by their highly conserved structure, which typically includes two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs). The NBDs are responsible for binding and hydrolyzing ATP, which provides the energy necessary for substrate translocation. The TMDs, on the other hand, form the pathway through which substrates are transported across the membrane.

The mechanism of action of ABC transporters involves the binding of ATP at the NBDs, which induces a conformational change in the transporter. This change in conformation allows the substrate to bind to the transporter. Following substrate binding, ATP is hydrolyzed, leading to another conformational change that translocates the substrate across the membrane. Finally, the release of ADP and inorganic phosphate resets the transporter to its original state.

Classification

ABC transporters are classified into several subfamilies based on their sequence similarity and domain organization. The major subfamilies include:

• ABCA: Involved in the transport of lipids and sterols.
• ABCB: Includes transporters such as P-glycoprotein, which is known for its role in multidrug resistance.
• ABCC: Contains transporters like the cystic fibrosis transmembrane conductance regulator (CFTR), which is implicated in cystic fibrosis.
• ABCD: Primarily involved in the transport of fatty acyl-CoAs into peroxisomes.
• ABCE and ABCF: Do not function as transporters but are involved in ribosome assembly and translation regulation.

Physiological Roles and Clinical Significance

ABC transporters play vital roles in various physiological processes, including lipid transport, drug metabolism, and the immune response. Their dysfunction or aberrant expression is associated with numerous diseases and conditions.

In cancer, overexpression of certain ABC transporters, such as P-glycoprotein, confers resistance to chemotherapy by actively pumping out anticancer drugs from cancer cells. In cystic fibrosis, mutations in the CFTR gene lead to defective chloride ion transport, resulting in thick mucus secretions that impair lung function.

Given their role in drug resistance, ABC transporters are also targets for the development of inhibitors aimed at overcoming multidrug resistance in cancer and infectious diseases.

Research and Therapeutic Applications

Research on ABC transporters continues to uncover their complex roles in health and disease. Efforts are underway to develop therapeutic strategies that can modulate the activity of these transporters to treat diseases such as cancer, cystic fibrosis, and infectious diseases caused by drug-resistant pathogens.