The selectivity of the Na+/K+-pump is controlled by binding site protonation and self-correcting occlusion

摘要

A protein called the sodium-potassium pump resides in the membrane that surrounds living cells. The role of this protein is to 'pump' sodium and potassium ions across the membrane to help restore their concentration inside and outside of the cell. About 25% of the body's energy is used to keep the pump going, rising to nearly 70% in the brain. Problems that affect the pump have been linked to several disorders, including heart, kidney and metabolic diseases, as well as severe neurological conditions. The sodium-potassium pump must be able to effectively pick out the correct ions to transport from a mixture of many different types of ions. However, it was not clear how the pump succeeds in doing this efficiently. Rui et al. have now used a computational method called molecular dynamics simulations to model how the sodium-potassium pump transports the desired ions across the cell membrane. The pump works via a so-called 'alternating-access' mechanism, repeatedly transitioning between inward-facing and outward-facing conformations. In each cycle, it binds three sodium ions from the cell’s interior and exports them to the outside. Then, the pump binds to two potassium ions from outside the cell and imports them inside. Although the bound sodium and potassium ions interact with similar binding sites in the pump, the pump sometimes preferentially binds sodium, and sometimes potassium. The study performed by Rui et al. shows that this preference is driven by how protons (hydrogen ions) bind to the amino acids that make up the binding site. The simulations also suggest that the pump uses a ‘self-correcting’ mechanism to prevent the pump from transporting the wrong types of ions. When incorrect ions are present at the binding sites, the pump cycle pauses temporarily until the ions detach from the pump. Only when the correct ions are bound will the pump cycle continue again. In the future, Rui et al. hope to use long time-scale molecular dynamics simulations to show the conformational transition in action. In addition, the 'self-correcting' mechanism will be directly tested by letting the wrong and correct ions compete for the binding sites to see whether the pump will transport only the correct ions.