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- EMDB-36752: Outward-facing SLC15A4 dimer -

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Basic information

Entry
Database: EMDB / ID: EMD-36752
TitleOutward-facing SLC15A4 dimer
Map data
Sample
  • Organelle or cellular component: endolysosomal transporter
    • Protein or peptide: lysosomal transporter
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL
Keywordsendolysosomal transporter / PROTEIN TRANSPORT
Function / homology
Function and homology information


L-histidine transmembrane transporter activity / histidine transport / mast cell homeostasis / L-histidine transmembrane export from vacuole / 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 ...L-histidine transmembrane transporter activity / histidine transport / mast cell homeostasis / L-histidine transmembrane export from vacuole / 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 / positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway / regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway / endolysosome membrane / positive regulation of innate immune response / peptide transport / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.95 Å
AuthorsZhang SS / Chen XD / Xie M
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)21532004, 31570733 China
CitationJournal: Nat Commun / Year: 2023
Title: Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling.
Authors: Xudong Chen / Min Xie / Sensen Zhang / Marta Monguió-Tortajada / Jian Yin / Chang Liu / Youqi Zhang / Maeva Delacrétaz / Mingyue Song / Yixue Wang / Lin Dong / Qiang Ding / Boda Zhou / ...Authors: Xudong Chen / Min Xie / Sensen Zhang / Marta Monguió-Tortajada / Jian Yin / Chang Liu / Youqi Zhang / Maeva Delacrétaz / Mingyue Song / Yixue Wang / Lin Dong / Qiang Ding / Boda Zhou / Xiaolin Tian / Haiteng Deng / Lina Xu / Xiaohui Liu / Zi Yang / Qing Chang / Jie Na / Wenwen Zeng / Giulio Superti-Furga / Manuele Rebsamen / Maojun Yang /
Abstract: Toll-like receptors (TLRs) are a class of proteins that play critical roles in recognizing pathogens and initiating innate immune responses. TASL, a recently identified innate immune adaptor protein ...Toll-like receptors (TLRs) are a class of proteins that play critical roles in recognizing pathogens and initiating innate immune responses. TASL, a recently identified innate immune adaptor protein for endolysosomal TLR7/8/9 signaling, is recruited by the lysosomal proton-coupled amino-acid transporter SLC15A4, and then activates IRF5, which in turn triggers the transcription of type I interferons and cytokines. Here, we report three cryo-electron microscopy (cryo-EM) structures of human SLC15A4 in the apo monomeric and dimeric state and as a TASL-bound complex. The apo forms are in an outward-facing conformation, with the dimeric form showing an extensive interface involving four cholesterol molecules. The structure of the TASL-bound complex reveals an unprecedented interaction mode with solute carriers. During the recruitment of TASL, SLC15A4 undergoes a conformational change from an outward-facing, lysosomal lumen-exposed state to an inward-facing state to form a binding pocket, allowing the N-terminal helix of TASL to be inserted into. Our findings provide insights into the molecular basis of regulatory switch involving a human solute carrier and offers an important framework for structure-guided drug discovery targeting SLC15A4-TASL-related human autoimmune diseases.
History
DepositionJul 6, 2023-
Header (metadata) releaseSep 27, 2023-
Map releaseSep 27, 2023-
UpdateDec 13, 2023-
Current statusDec 13, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36752.png

Downloads & links

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Map

FileDownload / File: emd_36752.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 240 pix.
= 263.496 Å		1.1 Å/pix.
x 240 pix.
= 263.496 Å		1.1 Å/pix.
x 240 pix.
= 263.496 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0979 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.475
Minimum - Maximum-2.032943 - 3.8551078
Average (Standard dev.)-0.0013388692 (±0.09211275)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 263.496 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_36752_half_map_1.map
Projections & Slices
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Half map: #2

Fileemd_36752_half_map_2.map
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Sample components

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Entire : endolysosomal transporter

EntireName: endolysosomal transporter
Components
  • Organelle or cellular component: endolysosomal transporter
    • Protein or peptide: lysosomal transporter
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CHOLESTEROL

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Supramolecule #1: endolysosomal transporter

SupramoleculeName: endolysosomal transporter / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: lysosomal transporter

MacromoleculeName: lysosomal transporter / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.233641 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MEGSGGGAGE RAPLLGARRA AAAAAAAGAF AGRRAACGAV LLTELLERAA FYGITSNLVL FLNGAPFCWE GAQASEALLL FMGLTYLGS PFGGWLADAR LGRARAILLS LALYLLGMLA FPLLAAPATR AALCGSARLL NCTAPGPDAA ARCCSPATFA G LVLVGLGV ...String:
MEGSGGGAGE RAPLLGARRA AAAAAAAGAF AGRRAACGAV LLTELLERAA FYGITSNLVL FLNGAPFCWE GAQASEALLL FMGLTYLGS PFGGWLADAR LGRARAILLS LALYLLGMLA FPLLAAPATR AALCGSARLL NCTAPGPDAA ARCCSPATFA G LVLVGLGV ATVKANITPF GADQVKDRGP EATRRFFNWF YWSINLGAIL SLGGIAYIQQ NVSFVTGYAI PTVCVGLAFV VF LCGQSVF ITKPPDGSAF TDMFKILTYS CCSQKRSGER QSNGEGIGVF QQSSKQSLFD SCKMSHGGPF TEEKVEDVKA LVK IVPVFL ALIPYWTVYF QMQTTYVLQS LHLRIPEISN ITTTPHTLPA AWLTMFDAVL ILLLIPLKDK LVDPILRRHG LLPS SLKRI AVGMFFVMCS AFAAGILESK RLNLVKEKTI NQTIGNVVYH AADLSLWWQV PQYLLIGISE IFASIAGLEF AYSAA PKSM QSAIMGLFFF FSGVGSFVGS GLLALVSIKA IGWMSSHTDF GNINGCYLNY YFFLLAAIQG ATLLLFLIIS VKYDHH RDH QRSRANGVPT SRRAGSLEVL FQGPGGGSGG GSWSHPQFEK GGGSGGGSWS HPQFEK

UniProtKB: Solute carrier family 15 member 4

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Macromolecule #2: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #3: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 3 / Number of copies: 4 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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: 7.2
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 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: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.95 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 83745
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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