In 1986, Kazumitsu Ueda, a Japanese cell biochemist, discovered that a Protein called ABCB1 can transport a variety of chemotherapy drugs from some cancer cells, making them resistant to treatment. How it did this has been a mystery for the past 35 years. Now, Ueda and its team published a review article entitled “ABCB1 / mdr1 / P-GP employees an ATP-dependent twist- and -squeeze mechanism to export hydrophobic drugs” in FEBS letters, summarizing their experience after years of research on this and other ATP binding cassette (ABC) transporters. Ueda is now working in the Institute of cell materials science, Kyoto University, Japan.
ABC transporters are very similar in different species and have various transport functions: importing nutrients into cells, exporting toxic compounds out of cells, and regulating lipid concentration in the cell membrane.
ABCB1 is one of these proteins. In the brain, testis, placenta, and other important organs, it is responsible for transporting toxic compounds to the outside of cells. But sometimes, it also transports chemotherapeutic drugs from cancer cells, making them resistant to treatment. The protein spans the cell membrane, reaching into the cell at one end and into the surrounding space at the other. Although scientists have known its function and structure for many years, how it works is still unclear.
Ueda and his team crystallize ABCB1 before and after it transports a compound. They then conducted X-ray tests to determine the difference between the two structures. They also analyzed ABCB1 fused with a fluorescent protein to monitor conformational changes during transport.
They found that compounds destined to be exported to the outside of the cell enter the cavity of the protein through a gate located in the part of ABCB1 in the cell membrane. The compound stays at the top of the cavity, where it attaches to it, triggering structural changes in the protein. This change requires energy, which comes from adenosine triphosphate (ATP). When magnesium ion combines with ATP, the part of ABCB1 in the cell will tightly self-pack and tilt, causing its cavity to contract and then close. This opens up the export of this protein. ATP is also involved in the gradual hardening of ABCB1 from the bottom to the top, leading to twisting and squeezing movements that expel the compound into extracellular space.
“This mechanism is different from that of other transporters,” Ueda said, “We hope that our research work can promote the study of other ABC proteins, such as those involved in cholesterol homeostasis”.
Reference
- Atsushi Kodan et al. ABCB1/MDR1/P-gp employs an ATP-dependent twist-and-squeeze mechanism to export hydrophobic drugs. FEBS Letters, 2020, doi:10.1002/1873-3468.14018.
