ABC proteins

Article

July 5, 2022

ABC proteins (ATP-binding cassette transporters, ABC transporters) are members of the protein superfamily, which is one of the largest and oldest families with representatives in all existing taxonomic divisions, from prokaryotes to humans. ABC transporters usually consist of multiple subunits, one or two of which are transmembrane proteins and one or two of which are membrane-bound ATPases. ATPase subunits use the energy of adenosine triphosphate (ATP) binding and hydrolysis to translocate various substrates across membranes, either for uptake or export of the substrate. Most, though not all, systems also have an extracytoplasmic receptor, a protein to which the solute binds. Some homologous ATPases function in processes unrelated to transport, such as RNA translation and DNA repair. ABC transporters are thought to be part of the ABC superfamily. That view is based on their protein sequences and on the organization of their ATP-binding cassette (ABC) domains, although integral membrane proteins probably evolved independently at some point, and thus there are several distinct protein families. There are indications that integral membrane proteins of ABC exporters have evolved independently at least three times. ABC1 exporters were created by intragenic triplication of 2 TMS precursors, resulting in the formation of 6 TMS proteins. ABC2 exporters arise from intragenic duplication of a 3 TMS precursor, and ABC3 exporters arise from a 4 TMS precursor that is duplicated either extragenically to give two 4 TMS proteins, both of which are essential for transport function, or intragenically to give 8 or 10 TMS proteins. Those 10 TMS proteins have two additional TMS domains between two 4 TMS repeat units. Similarly, it is possible that the integral membrane proteins of the ABC uptake system arose independently at least three times, judging by their high-resolution three-dimensional structures. ABC uptake transporters transport many different nutrients, biosynthetic precursors, rare metals and vitamins, while exporters transport lipids, sterols, drugs and many different primary and secondary metabolites. Some of these exporters in humans contribute to tumor resistance, cystic fibrosis and a range of other human inherited diseases. The high level of expression of genes encoding individual exporters in prokaryotic and eukaryotic organisms (including humans) leads to the development of resistance to multiple drugs, such as antibiotics and anti-cancer agents. Hundreds of ABC transporters are known in prokaryotes and eukaryotes. ABC genes are essential for many processes in the cell, and mutations in human genes cause or contribute to a number of serious genetic diseases. Forty-eight ABC genes are known in humans. Many of them have been characterized and shown to be causally related to diseases such as cystic fibrosis, adrenoleukodystrophy, Stargardt's disease, drug-resistant tumors, Dubin-Johnson syndrome, Biller's disease, progressive familial intrahepatic cholestasis, X-linked sideroblastic anemia, ataxia , and persistent and hyperinsulinemic hypoglycemia. ABC transporters are also involved in multidrug resistance and for this reason some of them were originally identified. When ABC transporter proteins are overexpressed in cancer cells, they can export anticancer drugs, making tumors resistant.

Function

ABC transporters use the energy of ATP binding and hydrolysis to transport various substrates across cell membranes. They are divided into three main functional categories. In prokaryotes, importers mediate the entry of nutrients into the cell. Substrates that can be transported are ions, amino acids, peptides, sugars, and other molecules, which are mostly hydrophilic. The membrane-spanning region of the ABC protein protects hydrophilic substrates from lipids in the membrane bilayer thereby opening a pathway through the cell membrane. Eukaryotes do not possess importers. Exporters or effluxers, which are present in p