- EMDB-40457: Cryo-EM structure of human NCX1 in apo inactivated state -
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Entry
Database: EMDB / ID: EMD-40457
Title
Cryo-EM structure of human NCX1 in apo inactivated state
Map data
Sample
Complex: human cardiac NCX1 in complex with antibody Fab fragment
Complex: human cardiac NCX1 in apo inactivated state
Protein or peptide: Sodium/calcium exchanger 1
Complex: antibody Fab fragment
Protein or peptide: Fab light chain
Protein or peptide: Fab heavy chain
Ligand: CALCIUM ION
Ligand: SODIUM ION
Ligand: water
Keywords
Na/Ca exchanger / sodium calcium exchanger / TRANSPORT PROTEIN
Function / homology
Function and homology information
relaxation of smooth muscle / vascular associated smooth muscle contraction / calcium ion export / regulation of cell communication by electrical coupling / calcium:sodium antiporter activity / membrane depolarization during cardiac muscle cell action potential / regulation of the force of heart contraction / sodium ion export across plasma membrane / cell communication by electrical coupling involved in cardiac conduction / negative regulation of protein serine/threonine kinase activity ...relaxation of smooth muscle / vascular associated smooth muscle contraction / calcium ion export / regulation of cell communication by electrical coupling / calcium:sodium antiporter activity / membrane depolarization during cardiac muscle cell action potential / regulation of the force of heart contraction / sodium ion export across plasma membrane / cell communication by electrical coupling involved in cardiac conduction / negative regulation of protein serine/threonine kinase activity / sodium ion import across plasma membrane / intracellular sodium ion homeostasis / calcium ion import / regulation of cardiac muscle contraction by calcium ion signaling / cardiac muscle cell development / calcium ion transport into cytosol / Sodium/Calcium exchangers / relaxation of cardiac muscle / calcium ion transmembrane import into cytosol / Reduction of cytosolic Ca++ levels / ankyrin binding / negative regulation of cytosolic calcium ion concentration / cellular response to caffeine / calcium ion import across plasma membrane / positive regulation of the force of heart contraction / intercalated disc / regulation of cardiac conduction / sodium ion transmembrane transport / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / positive regulation of bone mineralization / calcium ion homeostasis / monoatomic ion transport / muscle contraction / cardiac muscle contraction / axon terminus / Ion homeostasis / T-tubule / response to muscle stretch / cytoskeletal protein binding / regulation of heart rate / cell periphery / calcium ion transmembrane transport / cellular response to reactive oxygen species / sarcolemma / Z disc / intracellular calcium ion homeostasis / regulation of gene expression / transmembrane transporter binding / postsynapse / calmodulin binding / postsynaptic density / axon / neuronal cell body / synapse / dendrite / calcium ion binding / nucleoplasm / plasma membrane Similarity search - Function
Sodium/calcium exchanger, isoform 1 / : / Sodium/calcium exchanger protein / Sodium/calcium exchanger domain, C-terminal extension / C-terminal extension of sodium/calcium exchanger domain / Na-Ca exchanger/integrin-beta4 / Calx-beta domain / Domains in Na-Ca exchangers and integrin-beta4 / NCX, central ion-binding domain superfamily / Sodium/calcium exchanger membrane region ...Sodium/calcium exchanger, isoform 1 / : / Sodium/calcium exchanger protein / Sodium/calcium exchanger domain, C-terminal extension / C-terminal extension of sodium/calcium exchanger domain / Na-Ca exchanger/integrin-beta4 / Calx-beta domain / Domains in Na-Ca exchangers and integrin-beta4 / NCX, central ion-binding domain superfamily / Sodium/calcium exchanger membrane region / Sodium/calcium exchanger protein / CalX-like domain superfamily / DnaJ domain Similarity search - Domain/homology
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
R35GM140892
United States
Welch Foundation
I-1578
United States
Howard Hughes Medical Institute (HHMI)
United States
Citation
Journal: Nat Commun / Year: 2023 Title: Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1. Authors: Jing Xue / Weizhong Zeng / Yan Han / Scott John / Michela Ottolia / Youxing Jiang / Abstract: Na/Ca exchangers (NCX) transport Ca in or out of cells in exchange for Na. They are ubiquitously expressed and play an essential role in maintaining cytosolic Ca homeostasis. Although extensively ...Na/Ca exchangers (NCX) transport Ca in or out of cells in exchange for Na. They are ubiquitously expressed and play an essential role in maintaining cytosolic Ca 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 Ca. 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 Ca 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 [Ca], 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. Ca binding to the cytosolic second Ca-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.
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