The three-dimensional atomic structure of a protein important for organ function

NKCC1 is a human chloride ion transporter with the ability to
transport sodium, potassium, and chloride ions from the outside into cells.
For example, in the kidneys, NKCC1-type proteins ensure that these ions are reabsorbed from the urine, and typically NKCC1 is important
for osmotic cell volume regulation.
In the brain, NKCC1 and its associated proteins are important for chloride ion gradients, which are essential
for electrical signaling in neural networks.

Using cryo-electron microscopy (cryo-em), colleagues from Paul Neessen's laboratory and from the Fenton and Hartmann laboratories of Aarhus University (AU) and the Lindundorf-Larsen laboratory at the University of Copenhagen (KU) identified NKCC1 (a so-called Na+-K⁺-2 chlorine-^-cotransporter) and studied its function
.

A deep understanding of the three-dimensional atomic structure and dynamics of NKCC1, including the study of binding ions, lipids and water molecules, and intracellular ion transport, provides important new information about the function of NKCC1, which is driven
by a sodium gradient established by a sodium-potassium pump.

In the journal EMBO, the team revealed a surprising mechanism of ion release into cells, starting with one of two bound chloride ions, followed by a sodium ion, and finally another chloride and potassium ion
.
Researchers will now continue to try to identify new compounds that interfere with NKCC1 function, which may help treat kidney and brain diseases, among other things
.

The project was extremely challenging from the start and was launched
nearly 10 years ago as a collaboration between Neeson and Fenton Laboratories.
First author and PhD student Caroline Neumann (now graduated) and colleagues from Nissen's laboratory made an important collaboration with Professor Rune Hartman's laboratory (AU) to establish an advanced and efficient protein production expression system and conducted functional studies
of transporters in mammalian cells with Professor Robert Fenton's laboratory (AU Department of Biomedical Sciences).
。 Finally, a computational simulation
of NKCC1 kinetics and ion release was performed with the team of Professor Kresten Lindorff-Larsen from the University of Copenhagen.