Aarhus Universitets segl

Seminar: David Drew: New structural insights into ion recognition and allosteric regulation of cation/proton exchangers

Prof. David Drew, Department of Biochemistry and Biophysics, Stockholm University

Oplysninger om arrangementet

Tidspunkt

Fredag 3. februar 2023,  kl. 11:30 - 12:00

Sted

MBG Auditorium (1871-120)

Na+/H+ exchangers are present in all cells to regulate pH, sodium levels and cell volume, Despite intensive structural, biophysical and computational investigation an ion-bound state has never been experimentally observed, hampering deeper insights into ion specificity and catalysis. Here, I will present the cryo-EM structure of an K+/H+ exchanger KefC from E. coli at 3.2 Å resolution. By structural assignment of a coordinated K+ ion, MD simulations and SSM-based electrophysiology, we demonstrate how the ion-binding site in KefC is adapted for binding a dehydrated K+ ion, which contrasts with Na+/H+ exchangers, which are predicted to coordinate a partially hydrated Na+ ion. The substrate-K+ ion is completely enclosed within the transport domains, consistent with an elevator alternating-access mechanism. KefC harbours C-terminal RCK regulatory domains, similar to the TrkA domain of K+-channels, forming homodimers that are stabilised by AMP and GSH. In the current KefC structure, a pair of domain-swapped helices in the RCK domains inhibit transport by directly interacting with the ion-transport domains. Taken together, we propose that KefC is activated by detachment of the RCK domains and ion-selectivity exploits the biophysical properties likewise adapted by cation ion-channels.