The regulation of intracellular pH is a fundamental process in most living organisms. Almost all cells have transport proteins, known as NHEs, that couple the movement of protons against sodium ions to fine-tune the cells internal pH, sodium levels and cell volume. The dysfunction of NHEs has been linked to many diseases such as cancer, hypertension, heart failure, diabetes, and epilepsy. In particular, NHEs are prime drug targets for cancer therapies, since tumor cells typically upregulate NHE expression to adapt to the abnormal metabolism of a cancer cell. Consequently, inhibition or knockdown of NHEs interferes with cancer development and could provide a new therapeutic avenue.
“By elucidating the 3D structure of the sodium/proton exchanger NHE9, we can better understand how ions are transported across cellular membranes.” says David Drew, who was leading the study at Stockholm University. “Interestingly, the transport of sodium is carried out in a transport movement that resemble elevators, which load up, move and deposit the ions on the other-side of the membrane. It’s a mechanism that we first observed in working with bacterial transporters, which are evolutionary related to our own NHE proteins.” says David Drew.
https://www.nature.com/articles/nature12484#videos;
https://www.nature.com/articles/nsmb.3164.
We could see some important differences to the bacterial counterparts however. In particular by collaborating with Dr. Michael Landreh at Karolinska Institutet and Prof. Dame Carol Robinson’s group at Oxford University, we observed that this NHE protein requires specific lipids to help stabilize it. In collaboration with Prof. Oliver Beckstein’s group at Arizona State University we further applied computational approaches to model how sodium interacts with this NHE transporter.
The PhD student leading the work Iven Winkelmann worked closely with lab members Pascal Meier and Rei Matsuoka on this study to achieve these results. “Transport proteins are very mobile, which makes them challenging to isolate and determine what they look like.” as Iven explains. “Nowadays our work is more and more a real team effort and we are excited to be finally revealing what NHE9 looks like and making a contribution to the field after so many years of intensive effort”.
The work was a collaboration between Stockholm University, Karolinska Institiutet, Oxford University and Arizona State University and was principally funded by The Knut and Alice Wallenberg foundation and the European Research Council (ERC) Consolidator grant EXCHANGE to David Drew at SU. The article "Structure and elevator mechanism of the mammalian sodium/proton exchanger NHE9” is published in the scientific journal EMBO Journal on October 29th 2020.
DOI:10.15252/embj.2020105908
https://www.embopress.org/doi/10.15252/embj.2020105908
