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- PDB-8grx: APOE4 receptor in complex with APOE4 NTD -

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Basic information

Entry
Database: PDB / ID: 8grx
TitleAPOE4 receptor in complex with APOE4 NTD
Components
  • Apolipoprotein E
  • Leukocyte immunoglobulin-like receptor subfamily A member 6
KeywordsIMMUNE SYSTEM / Receptor complex
Function / homology
Function and homology information


inhibitory MHC class I receptor activity / 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 ...inhibitory MHC class I receptor activity / 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 / maintenance of location in cell / 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 / acylglycerol homeostasis / NMDA glutamate receptor clustering / very-low-density lipoprotein particle remodeling / phosphatidylcholine-sterol O-acyltransferase activator activity / Chylomicron clearance / positive regulation of phospholipid efflux / Chylomicron remodeling / response to caloric restriction / lipid transporter activity / cellular response to lipoprotein particle stimulus / positive regulation of low-density lipoprotein particle receptor catabolic process / very-low-density lipoprotein particle clearance / regulation of amyloid fibril formation / Chylomicron assembly / high-density lipoprotein particle clearance / chylomicron / phospholipid efflux / regulation of protein metabolic process / very-low-density lipoprotein particle receptor binding / high-density lipoprotein particle remodeling / lipoprotein catabolic process / AMPA glutamate receptor clustering / melanosome organization / positive regulation of cholesterol metabolic process / multivesicular body, internal vesicle / regulation of behavioral fear response / reverse cholesterol transport / positive regulation of amyloid-beta clearance / host-mediated activation of viral process / high-density lipoprotein particle assembly / low-density lipoprotein particle / lipoprotein biosynthetic process / cholesterol transfer activity / high-density lipoprotein particle / protein import / very-low-density lipoprotein particle / cholesterol catabolic process / heparan sulfate proteoglycan binding / low-density lipoprotein particle remodeling / amyloid precursor protein metabolic process / negative regulation of amyloid fibril formation / regulation of amyloid precursor protein catabolic process / positive regulation of membrane protein ectodomain proteolysis / regulation of Cdc42 protein signal transduction / synaptic transmission, cholinergic / HDL remodeling / negative regulation of endothelial cell migration / cholesterol efflux / regulation of cholesterol metabolic process / artery morphogenesis / negative regulation of protein metabolic process / triglyceride homeostasis / regulation of axon extension / Scavenging by Class A Receptors / triglyceride metabolic process / low-density lipoprotein particle receptor binding / positive regulation of amyloid fibril formation / regulation of innate immune response / virion assembly / positive regulation of dendritic spine development / negative regulation of amyloid-beta formation / negative regulation of endothelial cell proliferation / response to dietary excess / antioxidant activity / locomotory exploration behavior / negative regulation of MAP kinase activity / lipoprotein particle binding / negative regulation of blood vessel endothelial cell migration / positive regulation of endocytosis / 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 / regulation of neuronal synaptic plasticity / regulation of proteasomal protein catabolic process / negative regulation of protein secretion / long-term memory / fatty acid homeostasis / long-chain fatty acid transport / regulation of protein-containing complex assembly
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 / Immunoglobulins / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Apolipoprotein E / Leukocyte immunoglobulin-like receptor subfamily A member 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsZhou, J. / Wang, Y. / Huang, G. / Shi, Y.
Funding support China, 1items
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, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jul 5, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 30, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Apolipoprotein E
B: Leukocyte immunoglobulin-like receptor subfamily A member 6
C: Apolipoprotein E
D: Leukocyte immunoglobulin-like receptor subfamily A member 6


Theoretical massNumber of molelcules
Total (without water)120,6784
Polymers120,6784
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Apolipoprotein E / Apo-E


Mass: 16469.791 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: APOE / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P02649
#2: Protein Leukocyte immunoglobulin-like receptor subfamily A member 6 / Immunoglobulin-like transcript 8 / ILT-8 / Leukocyte Ig-like receptor


Mass: 43869.168 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LILRA6, ILT8 / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: Q6PI73
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: APOE4-LilrB3 complex / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.1366 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
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: 1800 nm / Nominal defocus min: 1500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: dev_3689: / Classification: refinement
EM software
IDNameCategory
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
12cryoSPARCclassification
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 462565 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0068738
ELECTRON MICROSCOPYf_angle_d0.70711872
ELECTRON MICROSCOPYf_dihedral_angle_d11.5641184
ELECTRON MICROSCOPYf_chiral_restr0.0411246
ELECTRON MICROSCOPYf_plane_restr0.0051552

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