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- EMDB-34216: APOE4 receptor in complex with APOE4 NTD -

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Basic information

Entry
Database: EMDB / ID: EMD-34216
TitleAPOE4 receptor in complex with APOE4 NTD
Map data
Sample
  • Complex: APOE4-LilrB3 complex
    • Protein or peptide: Apolipoprotein E
  • Protein or peptide: Leukocyte immunoglobulin-like receptor subfamily A member 6
KeywordsReceptor complex / IMMUNE SYSTEM
Function / homology
Function and homology information


chylomicron remnant / lipid transport involved in lipid storage / triglyceride-rich lipoprotein particle clearance / intermediate-density lipoprotein particle clearance / positive regulation of lipid transport across blood-brain barrier / positive regulation of heparan sulfate proteoglycan binding / regulation of cellular response to very-low-density lipoprotein particle stimulus / metal chelating activity / Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors / discoidal high-density lipoprotein particle ...chylomicron remnant / lipid transport involved in lipid storage / triglyceride-rich lipoprotein particle clearance / intermediate-density lipoprotein particle clearance / positive regulation of lipid transport across blood-brain barrier / positive regulation of heparan sulfate proteoglycan binding / regulation of cellular response to very-low-density lipoprotein particle stimulus / metal chelating activity / Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors / discoidal high-density lipoprotein particle / chylomicron remnant clearance / lipoprotein particle / maintenance of location in cell / very-low-density lipoprotein particle clearance / intermediate-density lipoprotein particle / very-low-density lipoprotein particle remodeling / regulation of amyloid-beta clearance / response to caloric restriction / Chylomicron clearance / negative regulation of triglyceride metabolic process / NMDA glutamate receptor clustering / chylomicron / Chylomicron remodeling / phosphatidylcholine-sterol O-acyltransferase activator activity / positive regulation of phospholipid efflux / Chylomicron assembly / lipid transporter activity / positive regulation of low-density lipoprotein particle receptor catabolic process / positive regulation of cholesterol metabolic process / regulation of behavioral fear response / high-density lipoprotein particle remodeling / high-density lipoprotein particle clearance / multivesicular body, internal vesicle / lipoprotein catabolic process / very-low-density lipoprotein particle receptor binding / phospholipid efflux / regulation of amyloid fibril formation / regulation of protein metabolic process / AMPA glutamate receptor clustering / low-density lipoprotein particle / positive regulation by host of viral process / cholesterol transfer activity / reverse cholesterol transport / positive regulation of amyloid-beta clearance / high-density lipoprotein particle assembly / very-low-density lipoprotein particle / positive regulation of CoA-transferase activity / melanosome organization / lipoprotein biosynthetic process / protein import / negative regulation of blood coagulation / low-density lipoprotein particle remodeling / high-density lipoprotein particle / negative regulation of amyloid fibril formation / negative regulation of cholesterol biosynthetic process / amyloid precursor protein metabolic process / heparan sulfate proteoglycan binding / regulation of Cdc42 protein signal transduction / triglyceride homeostasis / regulation of amyloid precursor protein catabolic process / cholesterol catabolic process / positive regulation of membrane protein ectodomain proteolysis / synaptic transmission, cholinergic / HDL remodeling / negative regulation of endothelial cell migration / cholesterol efflux / Scavenging by Class A Receptors / negative regulation of protein metabolic process / artery morphogenesis / triglyceride metabolic process / regulation of axon extension / regulation of cholesterol metabolic process / positive regulation of amyloid fibril formation / low-density lipoprotein particle receptor binding / positive regulation of dendritic spine development / virion assembly / regulation of innate immune response / regulation of neuronal synaptic plasticity / locomotory exploration behavior / lipoprotein particle binding / positive regulation of endocytosis / negative regulation of amyloid-beta formation / negative regulation of endothelial cell proliferation / antioxidant activity / cGMP-mediated signaling / response to dietary excess / negative regulation of blood vessel endothelial cell migration / negative regulation of long-term synaptic potentiation / negative regulation of platelet activation / positive regulation of cholesterol efflux / positive regulation of dendritic spine maintenance / intracellular transport / regulation of protein-containing complex assembly / negative regulation of protein secretion / long-term memory / fatty acid homeostasis / long-chain fatty acid transport / positive regulation of lipid biosynthetic process / synaptic cleft / regulation of proteasomal protein catabolic process
Similarity search - Function
Alpha-1B-glycoprotein/leukocyte immunoglobulin-like receptor / Apolipoprotein A/E / Apolipoprotein A1/A4/E domain / Immunoglobulin domain / Immunoglobulin / Immunoglobulin domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Immunoglobulin subtype / Immunoglobulin ...Alpha-1B-glycoprotein/leukocyte immunoglobulin-like receptor / Apolipoprotein A/E / Apolipoprotein A1/A4/E domain / Immunoglobulin domain / Immunoglobulin / Immunoglobulin domain / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Apolipoprotein E / Leukocyte immunoglobulin-like receptor subfamily A member 6
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsZhou J / Wang Y / Huang G / Shi Y
Funding support China, 1 items
OrganizationGrant numberCountry
Other government2020C04001 China
CitationJournal: Cell Res / Year: 2023
Title: LilrB3 is a putative cell surface receptor of APOE4.
Authors: Jiayao Zhou / Yumeng Wang / Gaoxingyu Huang / Min Yang / Yumin Zhu / Chen Jin / Dan Jing / Kai Ji / Yigong Shi /
Abstract: The three isoforms of apolipoprotein E (APOE2, APOE3, and APOE4) only differ in two amino acid positions but exert quite different immunomodulatory effects. The underlying mechanism of such APOE ...The three isoforms of apolipoprotein E (APOE2, APOE3, and APOE4) only differ in two amino acid positions but exert quite different immunomodulatory effects. The underlying mechanism of such APOE isoform dependence remains enigmatic. Here we demonstrate that APOE4, but not APOE2, specifically interacts with the leukocyte immunoglobulin-like receptor B3 (LilrB3). Two discrete immunoglobin-like domains of the LilrB3 extracellular domain (ECD) recognize a positively charged surface patch on the N-terminal domain (NTD) of APOE4. The atomic structure reveals how two APOE4 molecules specifically engage two LilrB3 molecules, bringing their intracellular signaling motifs into close proximity through formation of a hetero-tetrameric complex. Consistent with our biochemical and structural analyses, APOE4, but not APOE2, activates human microglia cells (HMC3) into a pro-inflammatory state in a LilrB3-dependent manner. Together, our study identifies LilrB3 as a putative immune cell surface receptor for APOE4, but not APOE2, and may have implications for understanding the biological functions as well as disease relevance of the APOE isoforms.
History
DepositionSep 2, 2022-
Header (metadata) releaseJul 5, 2023-
Map releaseJul 5, 2023-
UpdateJul 5, 2023-
Current statusJul 5, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

Downloads & links

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Map

FileDownload / File: emd_34216.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.0979 Å
Density
Contour LevelBy AUTHOR: 1.2
Minimum - Maximum-4.568849 - 7.2745657
Average (Standard dev.)0.0020957298 (±0.1161594)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 281.0624 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_34216_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: #1

Fileemd_34216_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire : APOE4-LilrB3 complex

EntireName: APOE4-LilrB3 complex
Components
  • Complex: APOE4-LilrB3 complex
    • Protein or peptide: Apolipoprotein E
  • Protein or peptide: Leukocyte immunoglobulin-like receptor subfamily A member 6

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Supramolecule #1: APOE4-LilrB3 complex

SupramoleculeName: APOE4-LilrB3 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 136.6 KDa

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Macromolecule #1: Apolipoprotein E

MacromoleculeName: Apolipoprotein E / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.469791 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
GQRWELALGR FWDYLRWVQT LSEQVQEELL SSQVTQELRA LMDETMKELK AYKSELEEQL TPVAEETRAR LSKELQAAQA RLGADMEDV RGRLVQYRGE VQAMLGQSTE ELRVRLASHL RKLRKRLLRD ADDLQKRLAV Y

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Macromolecule #2: Leukocyte immunoglobulin-like receptor subfamily A member 6

MacromoleculeName: Leukocyte immunoglobulin-like receptor subfamily A member 6
type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.869168 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: PFPKPTLWAE PGSVISWGSP VTIWCQGSLE AQEYRLDKEG SPEPLDRNNP LEPKNKARFS IPSMTEHHAG RYRCHYYSSA GWSEPSDPL ELVMTGFYNK PTLSALPSPV VASGGNMTLR CGSQKGYHHF VLMKEGEHQL PRTLDSQQLH SGGFQALFPV G PVNPSHRW ...String:
PFPKPTLWAE PGSVISWGSP VTIWCQGSLE AQEYRLDKEG SPEPLDRNNP LEPKNKARFS IPSMTEHHAG RYRCHYYSSA GWSEPSDPL ELVMTGFYNK PTLSALPSPV VASGGNMTLR CGSQKGYHHF VLMKEGEHQL PRTLDSQQLH SGGFQALFPV G PVNPSHRW RFTCYYYYMN TPQVWSHPSD PLEILPSGVS RKPSLLTLQG PVLAPGQSLT LQCGSDVGYD RFVLYKEGER DF LQRPGQQ PQAGLSQANF TLGPVSRSHG GQYRCYGAHN LSSEWSAPSD PLNILMAGQI YDTVSLSAQP GPTVASGENV TLL CQSWWQ FDTFLLTKEG AAHPPLRLRS MYGAHKYQAE FPMSPVTSAH AGTYRCYGSY SSNPHLLSFP SEPLELMVSG

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.5 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: NOT APPLICABLE / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC
Final angle assignmentType: NOT APPLICABLE / Software - Name: cryoSPARC
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 462565

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