Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1

Jing Xue, Weizhong Zeng, Yan Han, Scott John, Michela Ottolia and Youxing Jiang ()
Additional contact information
Jing Xue: The University of Texas Southwestern Medical Center
Weizhong Zeng: The University of Texas Southwestern Medical Center
Yan Han: The University of Texas Southwestern Medical Center
Scott John: University of California Los Angeles
Michela Ottolia: University of California Los Angeles
Youxing Jiang: The University of Texas Southwestern Medical Center

Nature Communications, 2023, vol. 14, issue 1, 1-11

Abstract: Abstract Na+/Ca2+ exchangers (NCX) transport Ca2+ in or out of cells in exchange for Na+. They are ubiquitously expressed and play an essential role in maintaining cytosolic Ca2+ homeostasis. Although extensively studied, little is known about the global structural arrangement of eukaryotic NCXs and the structural mechanisms underlying their regulation by various cellular cues including cytosolic Na+ and Ca2+. Here we present the cryo-EM structures of human cardiac NCX1 in both inactivated and activated states, elucidating key structural elements important for NCX ion exchange function and its modulation by cytosolic Ca2+ and Na+. We demonstrate that the interactions between the ion-transporting transmembrane (TM) domain and the cytosolic regulatory domain define the activity of NCX. In the inward-facing state with low cytosolic [Ca2+], a TM-associated four-stranded β-hub mediates a tight packing between the TM and cytosolic domains, resulting in the formation of a stable inactivation assembly that blocks the TM movement required for ion exchange function. Ca2+ binding to the cytosolic second Ca2+-binding domain (CBD2) disrupts this inactivation assembly which releases its constraint on the TM domain, yielding an active exchanger. Thus, the current NCX1 structures provide an essential framework for the mechanistic understanding of the ion transport and cellular regulation of NCX family proteins.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-023-41885-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41885-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-41885-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().