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- PDB-8jzr: Outward_facing SLC15A4 monomer -

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Basic information

Entry
Database: PDB / ID: 8jzr
TitleOutward_facing SLC15A4 monomer
ComponentsSLC15A4-ALFA tag-SLC15A4-twin-strep tag fusion protein
KeywordsPROTEIN TRANSPORT / endolysosomal 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 / positive regulation of toll-like receptor 8 signaling pathway / peptidoglycan transport / positive regulation of toll-like receptor 7 signaling pathway / regulation of isotype switching to IgG isotypes ...histidine transport / mast cell homeostasis / L-histidine transmembrane export from vacuole / L-histidine transmembrane transporter activity / peptidoglycan transmembrane transporter activity / Proton/oligopeptide cotransporters / positive regulation of toll-like receptor 8 signaling pathway / peptidoglycan transport / positive regulation of toll-like receptor 7 signaling pathway / regulation of isotype switching to IgG isotypes / 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)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.25 Å
AuthorsZhang, S.S. / Chen, X.D. / Xie, M.
Funding support China, 1items
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, 2023Deposition site: PDBJ / Processing site: PDBJ
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: SLC15A4-ALFA tag-SLC15A4-twin-strep tag fusion protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,4952
Polymers62,2741
Non-polymers2211
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein SLC15A4-ALFA tag-SLC15A4-twin-strep tag fusion protein


Mass: 62274.246 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: SLC15A4 (1-252 residues) + ALFA tag (SRLEEELRRRLTE) + SLC15A4(304-577 resides)+ twin-strep tag sequence
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) synthetic construct (others)
Gene: SLC15A4 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q8N697
#2: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN
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: endolysosomal transporter / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.2
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.25 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 107000 / Symmetry type: POINT

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