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Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1

Author

Listed:
  • Jing Xue

    (The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center)

  • Weizhong Zeng

    (The University of Texas Southwestern Medical Center
    The University of Texas Southwestern Medical Center)

  • Yan Han

    (The University of Texas Southwestern Medical Center
    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
    The University of Texas Southwestern Medical Center)

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.

Suggested Citation

  • Jing Xue & Weizhong Zeng & Yan Han & Scott John & Michela Ottolia & Youxing Jiang, 2023. "Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41885-4
    DOI: 10.1038/s41467-023-41885-4
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    References listed on IDEAS

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    1. Tong Mook Kang & Donald W. Hilgemann, 2004. "Multiple transport modes of the cardiac Na+/Ca2+ exchanger," Nature, Nature, vol. 427(6974), pages 544-548, February.
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    Cited by:

    1. Kyle Scranton & Scott John & Marina Angelini & Federica Steccanella & Soban Umar & Rui Zhang & Joshua I. Goldhaber & Riccardo Olcese & Michela Ottolia, 2024. "Cardiac function is regulated by the sodium-dependent inhibition of the sodium-calcium exchanger NCX1," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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