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- EMDB-40460: Cryo-EM map of human cardiac sodium calcium exchanger NCX1 in apo... -

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Basic information

Entry
Database: EMDB / ID: EMD-40460
TitleCryo-EM map of human cardiac sodium calcium exchanger NCX1 in apo, inactivated state (group I in the presence of 0.5mM Ca2+)
Map data
Sample
  • Complex: human cardiac sodium calcium exchanger NCX1 in apo, inactivated state ( group I in the presence of 0.5mM Ca2+) and bound Fab fragment
    • Complex: human cardiac sodium calcium exchanger NCX1 in apo, inactivated state ( group I in the presence of 0.5mM Ca2+)
      • Protein or peptide: human cardiac sodium calcium exchanger NCX1
    • Complex: antibody Fab fragment
KeywordsNa/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 / negative regulation of protein serine/threonine kinase activity / sodium ion import across plasma membrane ...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 / 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 / calcium ion transmembrane import into cytosol / relaxation of cardiac muscle / cell communication by electrical coupling involved in cardiac conduction / Reduction of cytosolic Ca++ levels / ankyrin binding / negative regulation of cytosolic calcium ion concentration / cellular response to caffeine / positive regulation of the force of heart contraction / intercalated disc / sodium ion transmembrane transport / calcium ion import across plasma membrane / regulation of cardiac conduction / calcium ion homeostasis / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / positive regulation of bone mineralization / monoatomic ion transport / cardiac muscle contraction / axon terminus / Ion homeostasis / T-tubule / cytoskeletal protein binding / response to muscle stretch / regulation of heart rate / muscle contraction / cell periphery / calcium ion transmembrane transport / sarcolemma / Z disc / cellular response to reactive oxygen species / intracellular calcium ion homeostasis / postsynapse / regulation of gene expression / transmembrane transporter binding / postsynaptic density / calmodulin binding / axon / neuronal cell body / synapse / calcium ion binding / dendrite / 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 protein ...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
Sodium/calcium exchanger 1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsXue J / Jiang Y
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM140892 United States
Welch FoundationI-1578 United States
Howard Hughes Medical Institute (HHMI) United States
CitationJournal: 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.
History
DepositionApr 12, 2023-
Header (metadata) releaseOct 11, 2023-
Map releaseOct 11, 2023-
UpdateNov 1, 2023-
Current statusNov 1, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

Downloads & links

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Map

FileDownload / File: emd_40460.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.35
Minimum - Maximum-0.7987287 - 1.6258652
Average (Standard dev.)0.0034303954 (±0.03536721)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 298.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_40460_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: #1

Fileemd_40460_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire : human cardiac sodium calcium exchanger NCX1 in apo, inactivated s...

EntireName: human cardiac sodium calcium exchanger NCX1 in apo, inactivated state ( group I in the presence of 0.5mM Ca2+) and bound Fab fragment
Components
  • Complex: human cardiac sodium calcium exchanger NCX1 in apo, inactivated state ( group I in the presence of 0.5mM Ca2+) and bound Fab fragment
    • Complex: human cardiac sodium calcium exchanger NCX1 in apo, inactivated state ( group I in the presence of 0.5mM Ca2+)
      • Protein or peptide: human cardiac sodium calcium exchanger NCX1
    • Complex: antibody Fab fragment

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Supramolecule #1: human cardiac sodium calcium exchanger NCX1 in apo, inactivated s...

SupramoleculeName: human cardiac sodium calcium exchanger NCX1 in apo, inactivated state ( group I in the presence of 0.5mM Ca2+) and bound Fab fragment
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: human cardiac sodium calcium exchanger NCX1 in apo, inactivated s...

SupramoleculeName: human cardiac sodium calcium exchanger NCX1 in apo, inactivated state ( group I in the presence of 0.5mM Ca2+)
type: complex / ID: 2 / Parent: 1 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: antibody Fab fragment

SupramoleculeName: antibody Fab fragment / type: complex / ID: 3 / Parent: 1
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: human cardiac sodium calcium exchanger NCX1

MacromoleculeName: human cardiac sodium calcium exchanger NCX1 / type: protein_or_peptide / ID: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MYNMRRLSLS PTFSMGFHLL VTVSLLFSHV DHVIAETEME GEGNETGECT GSYYCKKGVI LPIWEPQDPS FGDKIARATV YFVAMVYMFL GVSIIADRFM SSIEVITSQE KEITIKKPNG ETTKTTVRIW NETVSNLTLM ALGSSAPEIL LSVIEVCGHN FTAGDLGPST ...String:
MYNMRRLSLS PTFSMGFHLL VTVSLLFSHV DHVIAETEME GEGNETGECT GSYYCKKGVI LPIWEPQDPS FGDKIARATV YFVAMVYMFL GVSIIADRFM SSIEVITSQE KEITIKKPNG ETTKTTVRIW NETVSNLTLM ALGSSAPEIL LSVIEVCGHN FTAGDLGPST IVGSAAFNMF IIIALCVYVV PDGETRKIKH LRVFFVTAAW SIFAYTWLYI ILSVISPGVV EVWEGLLTFF FFPICVVFAW VADRRLLFYK YVYKRYRAGK QRGMIIEHEG DRPSSKTEIE MDGKVVNSHV ENFLDGALVL EVDERDQDDE EARREMARIL KELKQKHPDK EIEQLIELAN YQVLSQQQKS RAFYRIQATR LMTGATENDP VSKIFFEQGT YQCLENCGTV ALTIIRRGGD LTNTVFVDFR TEDGTANAGS DYEFTEGTVV FKPGDTQKEI RVGIIDDDIF EEDENFLVHL SNVKVSSEAS EDGILEANHV STLACLGSPS TATVTIFDDD HAGIFTFEEP VTHVSESIGI MEVKVLRTSG ARGNVIVPYK TIEGTARGGG EDFEDTCGEL EFQNDEIVKT ISVKVIDDEE YEKNKTFFLE IGEPRLVEMS EKKALLLNEL GGFTITGKYL FGQPVFRKVH AREHPILSTV ITIADEYDDK QPLTSKEEEE RRIAEMGRPI LGEHTKLEVI IEESYEFKST VDKLIKKTNL ALVVGTNSWR EQFIEAITVS AGEDDDDDEC GEEKLPSCFD YVMHFLTVFW KVLFAFVPPT EYWNGWACFI VSILMIGLLT AFIGDLASHF GCTIGLKDSV TAVVFVALGT SVPDTFASKV AATQDQYADA SIGNVTGSNA VNVFLGIGVA WSIAAIYHAA NGEQFKVSPG TLAFSVTLFT IFAFINVGVL LYRRRPEIGG ELGGPRTAKL LTSCLFVLLW LLYIFFSSLE AYCHIKGF

UniProtKB: Sodium/calcium exchanger 1

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 44844
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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