TY  - INPR
A1  - Fuss, Michael F.
A1  - Wieferig, Jan-Philip
A1  - Corey, Robin A.
A1  - Hellmich, Yvonne
A1  - Tascón, Igor
A1  - Sousa, Joana S.
A1  - Stansfeld, Phillip J.
A1  - Vonck, Janet
A1  - Hänelt, Inga
T1  - Cyclic di-AMP traps proton-coupled K+ transporters of the KUP family in an inward-occluded conformation
T2  - bioRxiv
N2  - Cyclic di-AMP is the only known essential second messenger in bacteria and archaea, regulating different proteins indispensable for numerous physiological processes. In particular, it controls various potassium and osmolyte transporters involved in osmoregulation. In Bacillus subtilis, the K+/H+ symporter KimA of the KUP family is inactivated by c-di-AMP. KimA sustains survival at potassium limitation at low external pH by mediating K+ ions uptake. However, at elevated intracellular K+ concentrations, further K+ accumulation would be toxic. In this study, we reveal the molecular basis of how c-di-AMP binding inhibits KimA. We report cryo-EM structures of KimA with bound c-di-AMP in detergent solution and reconstituted in amphipols. By combining structural data with functional assays and molecular dynamics simulations we reveal how c-di-AMP modulates transport. We show that an intracellular loop in the transmembrane domain interacts with c-di-AMP bound to the adjacent cytosolic domain. This reduces the mobility of transmembrane helices at the cytosolic side of the K+ binding site and therefore traps KimA in an inward-occluded conformation.
Y1  - 2023
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/73155
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-731555
IS  - 2023.01.09.523207
ER  -