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- PDB-8wx3: Cryo-EM structure of human SLC15A4 (outward-facing open) -

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Basic information

Entry
Database: PDB / ID: 8wx3
TitleCryo-EM structure of human SLC15A4 (outward-facing open)
ComponentsSolute carrier family 15 member 4
KeywordsMEMBRANE PROTEIN / Transporter
Function / homology
Function and homology information


histidine transport / mast cell homeostasis / L-histidine transmembrane export from vacuole / L-histidine transmembrane transporter activity / peptidoglycan transmembrane transporter activity / Proton/oligopeptide cotransporters / regulation of isotype switching to IgG isotypes / positive regulation of toll-like receptor 8 signaling pathway / peptidoglycan transport / positive regulation of toll-like receptor 7 signaling pathway ...histidine transport / mast cell homeostasis / L-histidine transmembrane export from vacuole / L-histidine transmembrane transporter activity / peptidoglycan transmembrane transporter activity / Proton/oligopeptide cotransporters / regulation of isotype switching to IgG isotypes / positive regulation of toll-like receptor 8 signaling pathway / peptidoglycan transport / positive regulation of toll-like receptor 7 signaling pathway / SLC15A4:TASL-dependent IRF5 activation / positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway / dipeptide import across plasma membrane / peptide:proton symporter activity / positive regulation of toll-like receptor 9 signaling pathway / dipeptide transmembrane transporter activity / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway / endolysosome membrane / positive regulation of innate immune response / specific granule membrane / monoatomic ion transport / protein transport / early endosome membrane / lysosomal membrane / innate immune response / Neutrophil degranulation / membrane / plasma membrane
Similarity search - Function
PTR2 family proton/oligopeptide symporters signature 2. / PTR2 family proton/oligopeptide symporter, conserved site / Proton-dependent oligopeptide transporter family / POT family / MFS transporter superfamily
Similarity search - Domain/homology
Solute carrier family 15 member 4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.83 Å
AuthorsSakaniwa, K. / Zhang, Z. / Ohto, U. / Shimizu, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Structure / Year: 2025
Title: The structures of the peptide transporters SLC15A3 and SLC15A4 reveal the recognition mechanisms for substrate and TASL.
Authors: Zhikuan Zhang / Shota Kasai / Kentaro Sakaniwa / Akiko Fujimura / Umeharu Ohto / Toshiyuki Shimizu /
Abstract: The solute carrier family 15 members 3 and 4 (SLC15A3 and SLC15A4) are closely related endolysosomal peptide transporters that transport free histidine and certain dipeptides from the lumen to ...The solute carrier family 15 members 3 and 4 (SLC15A3 and SLC15A4) are closely related endolysosomal peptide transporters that transport free histidine and certain dipeptides from the lumen to cytosol. Besides, SLC15A4 also functions as a scaffold protein for the recruitment of the adapter TASL for interferon regulatory factor 5 (IRF5) activation downstream of innate immune TLR7-9 signaling. However, the molecular basis for the substrate recognition and TASL recruitment by these membrane proteins is not well understood. Here, we report the cryoelectron microscopy (cryo-EM) structure of apo SLC15A3 and structures of SLC15A4 in the absence or presence of the substrate, revealing the specific dipeptide recognition mechanism. Each SLC15A3 and SLC15A4 protomer adopts an outward-facing conformation. Furthermore, we also present the cryo-EM structure of a SLC15A4-TASL complex. The N terminal region of TASL forms a helical structure that inserts deeply into the inward-facing cavity of SLC15A4.
History
DepositionOct 27, 2023Deposition site: PDBJ / Processing site: PDBJ
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Revision 1.1Oct 30, 2024Group: Data collection / Structure summary
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Solute carrier family 15 member 4
B: Solute carrier family 15 member 4


Theoretical massNumber of molelcules
Total (without water)129,7122
Polymers129,7122
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 Solute carrier family 15 member 4


Mass: 64856.176 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC15A4 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q8N697
Has protein modificationY

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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: Human SLC15A4 / 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: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 58 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 2.83 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 41843 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037686
ELECTRON MICROSCOPYf_angle_d0.57910456
ELECTRON MICROSCOPYf_dihedral_angle_d4.111038
ELECTRON MICROSCOPYf_chiral_restr0.0391224
ELECTRON MICROSCOPYf_plane_restr0.0041290

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