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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


immune response-regulating signaling pathway / lipid transport involved in lipid storage / intermediate-density lipoprotein particle clearance / positive regulation of lipid transport across blood-brain barrier / regulation of cellular response to very-low-density lipoprotein particle stimulus / metal chelating activity / triglyceride-rich lipoprotein particle clearance / discoidal high-density lipoprotein particle / lipoprotein particle / negative regulation of triglyceride metabolic process ...immune response-regulating signaling pathway / lipid transport involved in lipid storage / intermediate-density lipoprotein particle clearance / positive regulation of lipid transport across blood-brain barrier / regulation of cellular response to very-low-density lipoprotein particle stimulus / metal chelating activity / triglyceride-rich lipoprotein particle clearance / discoidal high-density lipoprotein particle / lipoprotein particle / negative regulation of triglyceride metabolic process / negative regulation of cholesterol biosynthetic process / regulation of amyloid-beta clearance / positive regulation of lipoprotein transport / Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors / chylomicron remnant clearance / chylomicron remnant / intermediate-density lipoprotein particle / maintenance of location in cell / very-low-density lipoprotein particle remodeling / acylglycerol homeostasis / NMDA glutamate receptor clustering / response to caloric restriction / phosphatidylcholine-sterol O-acyltransferase activator activity / Chylomicron clearance / positive regulation of phospholipid efflux / very-low-density lipoprotein particle clearance / Chylomicron remodeling / lipid transporter activity / positive regulation of cholesterol metabolic process / regulation of behavioral fear response / cellular response to lipoprotein particle stimulus / positive regulation of low-density lipoprotein particle receptor catabolic process / regulation of amyloid fibril formation / Chylomicron assembly / : / high-density lipoprotein particle clearance / chylomicron / phospholipid efflux / regulation of protein metabolic process / high-density lipoprotein particle remodeling / very-low-density lipoprotein particle receptor binding / AMPA glutamate receptor clustering / lipoprotein catabolic process / melanosome organization / multivesicular body, internal vesicle / reverse cholesterol transport / positive regulation of amyloid-beta clearance / positive regulation by host of viral process / high-density lipoprotein particle assembly / low-density lipoprotein particle / protein import / lipoprotein biosynthetic process / cholesterol transfer activity / high-density lipoprotein particle / very-low-density lipoprotein particle / cholesterol catabolic process / low-density lipoprotein particle remodeling / heparan sulfate proteoglycan binding / regulation of Cdc42 protein signal transduction / amyloid precursor protein metabolic process / negative regulation of amyloid fibril formation / triglyceride homeostasis / regulation of amyloid precursor protein catabolic process / positive regulation of membrane protein ectodomain proteolysis / synaptic transmission, cholinergic / HDL remodeling / negative regulation of endothelial cell migration / cholesterol efflux / regulation of axon extension / regulation of cholesterol metabolic process / negative regulation of protein metabolic process / artery morphogenesis / Scavenging by Class A Receptors / triglyceride metabolic process / positive regulation of dendritic spine development / low-density lipoprotein particle receptor binding / positive regulation of amyloid fibril formation / regulation of innate immune response / virion assembly / negative regulation of amyloid-beta formation / negative regulation of endothelial cell proliferation / locomotory exploration behavior / antioxidant activity / positive regulation of endocytosis / lipoprotein particle binding / response to dietary excess / negative regulation of blood vessel endothelial cell migration / regulation of neuronal synaptic plasticity / negative regulation of long-term synaptic potentiation / negative regulation of platelet activation / positive regulation of dendritic spine maintenance / negative regulation of blood coagulation / positive regulation of cholesterol efflux / negative regulation of MAP kinase activity / long-term memory / negative regulation of protein secretion / fatty acid homeostasis / regulation of protein-containing complex assembly / synaptic cleft / long-chain fatty acid transport
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 ...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 Z / 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-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_34216.png

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)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 256 pix.
= 281.062 Å		1.1 Å/pix.
x 256 pix.
= 281.062 Å		1.1 Å/pix.
x 256 pix.
= 281.062 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0979 Å
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Histogram

Histogram (log scale)
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
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Half map: #1

Fileemd_34216_half_map_2.map
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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

UniProtKB: Apolipoprotein E

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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

UniProtKB: Leukocyte immunoglobulin-like receptor subfamily A member 6

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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
Image recordingFilm or detector model: GATAN K3 (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: 1.8 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
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
Initial angle assignmentType: NOT APPLICABLE / Software - Name: cryoSPARC
Final angle assignmentType: NOT APPLICABLE / Software - Name: cryoSPARC
Final 3D classificationSoftware - Name: cryoSPARC

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