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- EMDB-30847: Structure of a human NHE1-CHP1 complex under pH 6.5 -

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Basic information

Entry
Database: EMDB / ID: EMD-30847
TitleStructure of a human NHE1-CHP1 complex under pH 6.5
Map data
Sample
  • Complex: Human NHE1-CHP1 complex under pH 6.5
    • Complex: Sodium/protein exchanger 1 (NHE1)
      • Protein or peptide: Sodium/hydrogen exchanger 1
    • Complex: Calcineurin B homologous protein 1 (CHP1)
      • Protein or peptide: Calcineurin B homologous protein 1
  • Ligand: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
KeywordsTransporter / MEMBRANE PROTEIN
Function / homology
Function and homology information


negative regulation of phosphatase activity / positive regulation of sodium:proton antiporter activity / positive regulation of mitochondrial membrane permeability / regulation of the force of heart contraction by cardiac conduction / Sodium/Proton exchangers / cation-transporting ATPase complex / membrane docking / negative regulation of protein autophosphorylation / Hyaluronan degradation / positive regulation of protein transport ...negative regulation of phosphatase activity / positive regulation of sodium:proton antiporter activity / positive regulation of mitochondrial membrane permeability / regulation of the force of heart contraction by cardiac conduction / Sodium/Proton exchangers / cation-transporting ATPase complex / membrane docking / negative regulation of protein autophosphorylation / Hyaluronan degradation / positive regulation of protein transport / cellular response to electrical stimulus / positive regulation of phospholipid biosynthetic process / transporter complex / regulation of cardiac muscle cell membrane potential / regulation of pH / positive regulation of action potential / positive regulation of glycoprotein biosynthetic process / hyaluronan catabolic process / maintenance of cell polarity / positive regulation of calcineurin-NFAT signaling cascade / sodium:proton antiporter activity / membrane organization / cellular response to cold / sodium ion export across plasma membrane / microtubule bundle formation / protein phosphatase 2B binding / regulation of stress fiber assembly / intracellular sodium ion homeostasis / negative regulation of calcineurin-NFAT signaling cascade / negative regulation of protein import into nucleus / response to acidic pH / sodium ion import across plasma membrane / regulation of focal adhesion assembly / regulation of cardiac muscle contraction by calcium ion signaling / cellular response to antibiotic / cardiac muscle cell contraction / positive regulation of cardiac muscle hypertrophy / small GTPase-mediated signal transduction / positive regulation of the force of heart contraction / endoplasmic reticulum-Golgi intermediate compartment / negative regulation of protein phosphorylation / protein kinase inhibitor activity / response to muscle stretch / protein complex oligomerization / potassium channel regulator activity / intercalated disc / positive regulation of protein targeting to membrane / potassium ion transport / protein export from nucleus / transport vesicle / negative regulation of protein kinase activity / cellular response to acidic pH / cytoplasmic microtubule organization / phosphatidylinositol-4,5-bisphosphate binding / negative regulation of protein ubiquitination / proton transmembrane transport / cellular response to epinephrine stimulus / T-tubule / regulation of intracellular pH / sodium ion transmembrane transport / cellular response to mechanical stimulus / phospholipid binding / kinase binding / calcium-dependent protein binding / microtubule cytoskeleton / cellular response to insulin stimulus / cell migration / positive regulation of cell growth / lamellipodium / cell differentiation / cellular response to hypoxia / microtubule binding / basolateral plasma membrane / molecular adaptor activity / membrane fusion / protein-macromolecule adaptor activity / protein stabilization / apical plasma membrane / positive regulation of apoptotic process / membrane raft / Golgi membrane / focal adhesion / calcium ion binding / negative regulation of apoptotic process / perinuclear region of cytoplasm / cell surface / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / extracellular exosome / membrane / identical protein binding / nucleus / plasma membrane / cytoplasm
Similarity search - Function
: / Sodium/hydrogen exchanger 1-like / Sodium/hydrogen exchanger, regulatory region / Regulatory region of Na+/H+ exchanger NHE binds to calmodulin / Na+/H+ exchanger / Cation/H+ exchanger, CPA1 family / Cation/H+ exchanger / Sodium/hydrogen exchanger, transmembrane / EF-hand domain pair / EF-hand, calcium binding motif ...: / Sodium/hydrogen exchanger 1-like / Sodium/hydrogen exchanger, regulatory region / Regulatory region of Na+/H+ exchanger NHE binds to calmodulin / Na+/H+ exchanger / Cation/H+ exchanger, CPA1 family / Cation/H+ exchanger / Sodium/hydrogen exchanger, transmembrane / EF-hand domain pair / EF-hand, calcium binding motif / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair
Similarity search - Domain/homology
Sodium/hydrogen exchanger 1 / Calcineurin B homologous protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsDong Y / Gao Y / Li B / Zhang XC / Zhao Y
CitationJournal: Nat Commun / Year: 2021
Title: Structure and mechanism of the human NHE1-CHP1 complex.
Authors: Yanli Dong / Yiwei Gao / Alina Ilie / DuSik Kim / Annie Boucher / Bin Li / Xuejun C Zhang / John Orlowski / Yan Zhao /
Abstract: Sodium/proton exchanger 1 (NHE1) is an electroneutral secondary active transporter present on the plasma membrane of most mammalian cells and plays critical roles in regulating intracellular pH and ...Sodium/proton exchanger 1 (NHE1) is an electroneutral secondary active transporter present on the plasma membrane of most mammalian cells and plays critical roles in regulating intracellular pH and volume homeostasis. Calcineurin B-homologous protein 1 (CHP1) is an obligate binding partner that promotes NHE1 biosynthetic maturation, cell surface expression and pH-sensitivity. Dysfunctions of either protein are associated with neurological disorders. Here, we elucidate structures of the human NHE1-CHP1 complex in both inward- and inhibitor (cariporide)-bound outward-facing conformations. We find that NHE1 assembles as a symmetrical homodimer, with each subunit undergoing an elevator-like conformational change during cation exchange. The cryo-EM map reveals the binding site for the NHE1 inhibitor cariporide, illustrating how inhibitors block transport activity. The CHP1 molecule differentially associates with these two conformational states of each NHE1 monomer, and this association difference probably underlies the regulation of NHE1 pH-sensitivity by CHP1.
History
DepositionJan 3, 2021-
Header (metadata) releaseJun 23, 2021-
Map releaseJun 23, 2021-
UpdateMar 27, 2024-
Current statusMar 27, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.045
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.045
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7dsv
  • Surface level: 0.045
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7dsv
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30847.png

Downloads & links

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Map

FileDownload / File: emd_30847.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1 Å/pix.
x 256 pix.
= 256. Å		1 Å/pix.
x 256 pix.
= 256. Å		1 Å/pix.
x 256 pix.
= 256. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.045 / Movie #1: 0.045
Minimum - Maximum-0.2149519 - 0.3352891
Average (Standard dev.)0.00021320212 (±0.007281356)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 256.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z111
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z256.000256.000256.000
α/β/γ90.00090.00090.000
start NX/NY/NZ192139186
NX/NY/NZ211274246
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.2150.3350.000

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Supplemental data

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Additional map: #1

Fileemd_30847_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human NHE1-CHP1 complex under pH 6.5

EntireName: Human NHE1-CHP1 complex under pH 6.5
Components
  • Complex: Human NHE1-CHP1 complex under pH 6.5
    • Complex: Sodium/protein exchanger 1 (NHE1)
      • Protein or peptide: Sodium/hydrogen exchanger 1
    • Complex: Calcineurin B homologous protein 1 (CHP1)
      • Protein or peptide: Calcineurin B homologous protein 1
  • Ligand: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

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Supramolecule #1: Human NHE1-CHP1 complex under pH 6.5

SupramoleculeName: Human NHE1-CHP1 complex under pH 6.5 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: CHP1 in this map was locally refined using symmetry expansion to improve resolution.
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 230 KDa

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Supramolecule #2: Sodium/protein exchanger 1 (NHE1)

SupramoleculeName: Sodium/protein exchanger 1 (NHE1) / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 182 KDa

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Supramolecule #3: Calcineurin B homologous protein 1 (CHP1)

SupramoleculeName: Calcineurin B homologous protein 1 (CHP1) / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2

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Macromolecule #1: Sodium/hydrogen exchanger 1

MacromoleculeName: Sodium/hydrogen exchanger 1 / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.893367 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: KAFPVLGIDY THVRTPFEIS LWILLACLMK IGFHVIPTIS SIVPESCLLI VVGLLVGGLI KGVGETPPFL QSDVFFLFLL PPIILDAGY FLPLRQFTEN LGTILIFAVV GTLWNAFFLG GLMYAVCLVG GEQINNIGLL DNLLFGSIIS AVDPVAVLAV F EEIHINEL ...String:
KAFPVLGIDY THVRTPFEIS LWILLACLMK IGFHVIPTIS SIVPESCLLI VVGLLVGGLI KGVGETPPFL QSDVFFLFLL PPIILDAGY FLPLRQFTEN LGTILIFAVV GTLWNAFFLG GLMYAVCLVG GEQINNIGLL DNLLFGSIIS AVDPVAVLAV F EEIHINEL LHILVFGESL LNDAVTVVLY HLFEEFANYE HVGIVDIFLG FLSFFVVALG GVLVGVVYGV IAAFTSRFTS HI RVIEPLF VFLYSYMAYL SAELFHLSGI MALIASGVVM RPYVEANISH KSHTTIKYFL KMWSSVSETL IFIFLGVSTV AGS HHWNWT FVISTLLFCL IARVLGVLGL TWFINKFRIV KLTPKDQFII AYGGLRGAIA FSLGYLLDKK HFPMCDLFLT AIIT VIFFT VFVQGMTIRP LVDLLAVKKK QETKRSINEE IHTQFLDHLL TGIEDICGHY GHHHWKDKLN RFNKKYV

UniProtKB: Sodium/hydrogen exchanger 1

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Macromolecule #2: Calcineurin B homologous protein 1

MacromoleculeName: Calcineurin B homologous protein 1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.36983 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
DEELEEIKKE TGFSHSQITR LYSRFTSLDK GENGTLSRED FQRIPELAIN PLGDRIINAF FPEGEDQVNF RGFMRTLAHF RPIEDNEKS KDVNGPEPLN SRSNKLHFAF RLYDLDKDEK ISRDELLQVL RMMVGVNISD EQLGSIADRT IQEADQDGDS A ASFTEFVK VLEKVDVEQK MSIRFLH

UniProtKB: Calcineurin B homologous protein 1

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Macromolecule #3: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine

MacromoleculeName: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / type: ligand / ID: 3 / Number of copies: 16 / Formula: LBN
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-LBN:
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine / phospholipid*YM

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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

Concentration6 mg/mL
BufferpH: 6.5
GridModel: Quantifoil / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: OTHER
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK III
DetailsThe NHE1-CHP1 complex was reconstituted into lipid nanodiscs.

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Digitization - Frames/image: 1-32 / Number grids imaged: 1 / Number real images: 2205 / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 µm / Nominal magnification: 13000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
In silico model: The insilico model was generated using Ab initio reconstruction in cryoSPARC.
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 100503
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software: (Name: RELION (ver. 3.1), cryoSPARC (ver. 2.15))
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.1)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-7dsv:
Structure of a human NHE1-CHP1 complex under pH 6.5

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