TY - JOUR
T1 - Structure, mechanism and lipid-mediated remodeling of the mammalian Na+/H+ exchanger NHA2
AU - Matsuoka, Rei
AU - Fudim, Roman
AU - Jung, Sukkyeong
AU - Zhang, Chenou
AU - Bazzone, Andre
AU - Chatzikyriakidou, Yurie
AU - Robinson, Carol V.
AU - Nomura, Norimichi
AU - Iwata, So
AU - Landreh, Michael
AU - Orellana, Laura
AU - Beckstein, Oliver
AU - Drew, David
N1 - Funding Information:
We are grateful for the salt-sensitive yeast Abc11 strain from O. Zimmermannova and to the Cryo-EM Swedish National Facility at SciLife Stockholm for cryo-EM data collection as well as the Umeå Core Facility for Electron Microscopy (UCEM) and the European Synchrotron Radiation Facility (ESRF). This work was funded by grants from The Swedish Research council (VR distinguished grant) and a European Research Council (ERC) Consolidator Grant EXCHANGE (grant no. ERC-CoG-820187) to D.D. The research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award no. R01GM118772 to O.B. MD simulations were performed using SDSC Expanse at the San Diego Supercomputing Center (allocation TG-MCB130177 to O.B.), a resource of the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant no. ACI-1548562. We also acknowledge Research Computing at Arizona State University for providing high performance computing and storage resources that have contributed to the research results reported within this Article. This work was partly supported by grants from Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from the Japan Agency of Medical Research and Development (AMED; grant no. JP20am0101079). This research was also supported by Cancerfonden Junior Investigator Award (21 0305 JIA 01 H) and Jeanssons Foundations Grants to L.O. eBDIMS simulations were performed using the Swedish National Infrastructure for Computing (allocation SNIC 2021/5-87 to L.O.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Funding Information:
We are grateful for the salt-sensitive yeast Abc11 strain from O. Zimmermannova and to the Cryo-EM Swedish National Facility at SciLife Stockholm for cryo-EM data collection as well as the Umeå Core Facility for Electron Microscopy (UCEM) and the European Synchrotron Radiation Facility (ESRF). This work was funded by grants from The Swedish Research council (VR distinguished grant) and a European Research Council (ERC) Consolidator Grant EXCHANGE (grant no. ERC-CoG-820187) to D.D. The research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award no. R01GM118772 to O.B. MD simulations were performed using SDSC Expanse at the San Diego Supercomputing Center (allocation TG-MCB130177 to O.B.), a resource of the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant no. ACI-1548562. We also acknowledge Research Computing at Arizona State University for providing high performance computing and storage resources that have contributed to the research results reported within this Article. This work was partly supported by grants from Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from the Japan Agency of Medical Research and Development (AMED; grant no. JP20am0101079). This research was also supported by Cancerfonden Junior Investigator Award (21 0305 JIA 01 H) and Jeanssons Foundations Grants to L.O. eBDIMS simulations were performed using the Swedish National Infrastructure for Computing (allocation SNIC 2021/5-87 to L.O.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/2
Y1 - 2022/2
N2 - The Na+/H+ exchanger SLC9B2, also known as NHA2, correlates with the long-sought-after Na+/Li+ exchanger linked to the pathogenesis of diabetes mellitus and essential hypertension in humans. Despite the functional importance of NHA2, structural information and the molecular basis for its ion-exchange mechanism have been lacking. Here we report the cryo-EM structures of bison NHA2 in detergent and in nanodiscs, at 3.0 and 3.5 Å resolution, respectively. The bison NHA2 structure, together with solid-state membrane-based electrophysiology, establishes the molecular basis for electroneutral ion exchange. NHA2 consists of 14 transmembrane (TM) segments, rather than the 13 TMs previously observed in mammalian Na+/H+ exchangers (NHEs) and related bacterial antiporters. The additional N-terminal helix in NHA2 forms a unique homodimer interface with a large intracellular gap between the protomers, which closes in the presence of phosphoinositol lipids. We propose that the additional N-terminal helix has evolved as a lipid-mediated remodeling switch for the regulation of NHA2 activity.
AB - The Na+/H+ exchanger SLC9B2, also known as NHA2, correlates with the long-sought-after Na+/Li+ exchanger linked to the pathogenesis of diabetes mellitus and essential hypertension in humans. Despite the functional importance of NHA2, structural information and the molecular basis for its ion-exchange mechanism have been lacking. Here we report the cryo-EM structures of bison NHA2 in detergent and in nanodiscs, at 3.0 and 3.5 Å resolution, respectively. The bison NHA2 structure, together with solid-state membrane-based electrophysiology, establishes the molecular basis for electroneutral ion exchange. NHA2 consists of 14 transmembrane (TM) segments, rather than the 13 TMs previously observed in mammalian Na+/H+ exchangers (NHEs) and related bacterial antiporters. The additional N-terminal helix in NHA2 forms a unique homodimer interface with a large intracellular gap between the protomers, which closes in the presence of phosphoinositol lipids. We propose that the additional N-terminal helix has evolved as a lipid-mediated remodeling switch for the regulation of NHA2 activity.
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U2 - 10.1038/s41594-022-00738-2
DO - 10.1038/s41594-022-00738-2
M3 - Article
C2 - 35173351
AN - SCOPUS:85124778658
SN - 1545-9993
VL - 29
SP - 108
EP - 120
JO - Nature Structural Biology
JF - Nature Structural Biology
IS - 2
ER -