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- PDB-9s0r: Cryo-EM structure of human NHE6 in C1 symmetry -

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Basic information

Entry
Database: PDB / ID: 9s0r
TitleCryo-EM structure of human NHE6 in C1 symmetry
ComponentsSodium/hydrogen exchanger 6
KeywordsTRANSPORT PROTEIN / NHE / C1 symmetry / homodimer / transporter
Function / homology
Function and homology information


Defective SLC9A6 causes X-linked, syndromic mental retardation,, Christianson type (MRXSCH) / Sodium/Proton exchangers / dendrite extension / potassium:proton antiporter activity / axon extension / sodium:proton antiporter activity / sodium ion import across plasma membrane / establishment of cell polarity / neuron projection morphogenesis / regulation of intracellular pH ...Defective SLC9A6 causes X-linked, syndromic mental retardation,, Christianson type (MRXSCH) / Sodium/Proton exchangers / dendrite extension / potassium:proton antiporter activity / axon extension / sodium:proton antiporter activity / sodium ion import across plasma membrane / establishment of cell polarity / neuron projection morphogenesis / regulation of intracellular pH / sodium ion transmembrane transport / recycling endosome / recycling endosome membrane / late endosome membrane / early endosome membrane / endosome membrane / endoplasmic reticulum membrane / identical protein binding / plasma membrane
Similarity search - Function
Sodium/hydrogen exchanger 6/7/9 / Na+/H+ exchanger / Cation/H+ exchanger, CPA1 family / Cation/H+ exchanger / Sodium/hydrogen exchanger, transmembrane
Similarity search - Domain/homology
Sodium/hydrogen exchanger 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsFeilen, L.P. / Sach, L. / Tranchant, E.E. / Lalic, M.R. / Havelund, J.F. / Brauer, C.M. / Ginsthofer, M. / Ostendorf, J. / Ma, L. / Morrow, E.M. ...Feilen, L.P. / Sach, L. / Tranchant, E.E. / Lalic, M.R. / Havelund, J.F. / Brauer, C.M. / Ginsthofer, M. / Ostendorf, J. / Ma, L. / Morrow, E.M. / Faergeman, N.J. / Pedersen, S.F. / Kragelund, B.B. / Autzen, H.E.
Funding support Denmark, European Union, 5items
OrganizationGrant numberCountry
Novo Nordisk FoundationNNF20OC0060692 Denmark
The Carlsberg FoundationCF20-0533 Denmark
Independent Research Fund Denmark - Medical Sciences1131-00023B Denmark
European Research Council (ERC)101151923European Union
Danish Council for Independent Research3103-00217B Denmark
CitationJournal: Nat Commun / Year: 2026
Title: Integrative structural analysis of human endosomal NHE6 reveals a lipid-associated gate and disordered C-terminus.
Authors: Lukas P Feilen / Lara K Sach / Emil E Tranchant / Milena R Lalic / Jesper F Havelund / Céline M Jeria Cerda / Marie Ginsthofer / Jan Ostendorf / Li Ma / Eric M Morrow / Nils J Færgeman / ...Authors: Lukas P Feilen / Lara K Sach / Emil E Tranchant / Milena R Lalic / Jesper F Havelund / Céline M Jeria Cerda / Marie Ginsthofer / Jan Ostendorf / Li Ma / Eric M Morrow / Nils J Færgeman / Stine F Pedersen / Birthe B Kragelund / Henriette E Autzen /
Abstract: Human NHE6 (HsNHE6) is an endosomal Na⁺/H⁺ exchanger essential for maintaining luminal pH and endo-lysosomal trafficking in neurons. HsNHE6 mutations are implicated in devastating neurological ...Human NHE6 (HsNHE6) is an endosomal Na⁺/H⁺ exchanger essential for maintaining luminal pH and endo-lysosomal trafficking in neurons. HsNHE6 mutations are implicated in devastating neurological syndromes, but mechanistically the transporter remains poorly understood. Here, we present the single-particle cryo-electron microscopy (cryo-EM) structure of HsNHE6 at 3.4 Å, captured in an inward-facing conformation. The structure reveals a homodimeric architecture with 13 transmembrane helices per protomer, with the conserved ion-binding site located at the interface of the core and dimerization domains. Functional assays demonstrate that HsNHE6 reconstituted in liposomes exchanges Na⁺, K⁺, Li⁺, and Rb for H, with kinetic analysis revealing a preference for K⁺. A structured C-terminal helix interacts with the transmembrane core, jointly forming a hydrophobic cavity containing two non-protein cryo-EM densities consistent with bound lipids that may modulate cation access to the ion-binding site. The remaining distal C-terminus of HsNHE6 is intrinsically disordered, as revealed by NMR and small-angle X-ray scattering, and extends up to 170 Å into the cytosol. Our integrative structural model of full-length HsNHE6 provides a framework for understanding HsNHE6-mediated ion exchange and its disruption in Christianson syndrome.
History
DepositionJul 16, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 29, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Jul 29, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Sep 23, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Sodium/hydrogen exchanger 6
B: Sodium/hydrogen exchanger 6


Theoretical massNumber of molelcules
Total (without water)155,9772
Polymers155,9772
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Sodium/hydrogen exchanger 6 / Na(+)/H(+) exchanger 6 / NHE-6 / Solute carrier family 9 member 6


Mass: 77988.508 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC9A6, KIAA0267, NHE6 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q92581
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Homodimeric human NHE6 in C1 symmetry / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
120 mM2-[4-(2-Hydroxyethyl)piperazin-1-yl]ethane-1-sulfonic acidHEPES1
2150 mMsodium chlorideNaCl1
30.034 mMglyco-diosgeninGDN1
40.008 mMcholesteryl hemisuccinate Tris saltCHS1
SpecimenConc.: 2.63 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 49 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4933
EM imaging opticsEnergyfilter name: TFS Selectris X

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Processing

EM software
IDNameVersionCategory
1RELION5.0-betaparticle selection
2EPUimage acquisition
4RELION5.0-betaCTF correction
9RELION5.0-betainitial Euler assignment
10RELION5.0-betafinal Euler assignment
12RELION5.0-beta3D reconstruction
13PHENIX1.21.1_5286model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 732718
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 76044 / Num. of class averages: 1 / Symmetry type: POINT
RefinementHighest resolution: 3.5 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0027254
ELECTRON MICROSCOPYf_angle_d0.4579844
ELECTRON MICROSCOPYf_dihedral_angle_d4.35969
ELECTRON MICROSCOPYf_chiral_restr0.0351142
ELECTRON MICROSCOPYf_plane_restr0.0031206

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