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- EMDB-48724: Lecithin:Cholesterol Acyltransferase Bound to Apolipoprotein A-I ... -

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Basic information

Entry
Database: EMDB / ID: EMD-48724
TitleLecithin:Cholesterol Acyltransferase Bound to Apolipoprotein A-I dimer in HDL
Map data
Sample
  • Complex: Complex of 2 Lecithin:Cholesterol Acyltransferase molecules bound to Apolipoprotein dimer in HDL
    • Protein or peptide: Phosphatidylcholine-sterol acyltransferase
  • Protein or peptide: Apolipoprotein A-I
  • Ligand: (4S,7R)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-3,5,8-TRIOXA-4-PHOSPHAHEXACOSAN-1-AMINIUM 4-OXIDE
KeywordsComplex / Lecithin:Cholesterol Acyltransferase / Apolipoprotein A-I / HDL / LIPID TRANSPORT
Function / homology
Function and homology information


phosphatidylcholine-sterol O-acyltransferase / phosphatidylcholine-sterol O-acyltransferase activity / regulation of high-density lipoprotein particle assembly / platelet-activating factor acetyltransferase activity / Defective ABCA1 causes TGD / sterol ester esterase activity / high-density lipoprotein particle receptor binding / peptidyl-methionine modification / HDL clearance / 1-alkyl-2-acetylglycerophosphocholine esterase ...phosphatidylcholine-sterol O-acyltransferase / phosphatidylcholine-sterol O-acyltransferase activity / regulation of high-density lipoprotein particle assembly / platelet-activating factor acetyltransferase activity / Defective ABCA1 causes TGD / sterol ester esterase activity / high-density lipoprotein particle receptor binding / peptidyl-methionine modification / HDL clearance / 1-alkyl-2-acetylglycerophosphocholine esterase / spherical high-density lipoprotein particle / Scavenging by Class B Receptors / 1-alkyl-2-acetylglycerophosphocholine esterase activity / negative regulation of response to cytokine stimulus / protein oxidation / regulation of intestinal cholesterol absorption / vitamin transport / blood vessel endothelial cell migration / apolipoprotein A-I binding / cholesterol import / negative regulation of heterotypic cell-cell adhesion / apolipoprotein receptor binding / apolipoprotein A-I receptor binding / ABC transporters in lipid homeostasis / A2-type glycerophospholipase activity / negative regulation of cell adhesion molecule production / negative regulation of cytokine production involved in immune response / HDL assembly / phosphatidylcholine metabolic process / high-density lipoprotein particle binding / negative regulation of very-low-density lipoprotein particle remodeling / aflatoxin metabolic process / glucocorticoid metabolic process / very-low-density lipoprotein particle remodeling / acylglycerol homeostasis / phosphatidylcholine biosynthetic process / phosphatidylcholine-sterol O-acyltransferase activator activity / positive regulation of phospholipid efflux / Chylomicron remodeling / cellular response to lipoprotein particle stimulus / Chylomicron assembly / high-density lipoprotein particle clearance / phospholipid efflux / chylomicron / high-density lipoprotein particle remodeling / reverse cholesterol transport / positive regulation of cholesterol metabolic process / lipid storage / high-density lipoprotein particle assembly / phospholipid homeostasis / chemorepellent activity / low-density lipoprotein particle / lipoprotein biosynthetic process / cholesterol transfer activity / cholesterol transport / high-density lipoprotein particle / very-low-density lipoprotein particle / endothelial cell proliferation / regulation of Cdc42 protein signal transduction / HDL remodeling / cholesterol efflux / adrenal gland development / Scavenging by Class A Receptors / triglyceride homeostasis / negative chemotaxis / negative regulation of interleukin-1 beta production / response to copper ion / cholesterol binding / cholesterol biosynthetic process / amyloid-beta formation / positive regulation of Rho protein signal transduction / positive regulation of cholesterol efflux / endocytic vesicle / negative regulation of tumor necrosis factor-mediated signaling pathway / Scavenging of heme from plasma / Retinoid metabolism and transport / cholesterol metabolic process / positive regulation of stress fiber assembly / phospholipid metabolic process / heat shock protein binding / endocytic vesicle lumen / positive regulation of substrate adhesion-dependent cell spreading / response to glucocorticoid / positive regulation of phagocytosis / cholesterol homeostasis / integrin-mediated signaling pathway / Post-translational protein phosphorylation / lipid metabolic process / Heme signaling / PPARA activates gene expression / phospholipid binding / negative regulation of inflammatory response / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Platelet degranulation / extracellular vesicle / amyloid-beta binding / cytoplasmic vesicle / secretory granule lumen / blood microparticle / early endosome
Similarity search - Function
Lecithin:cholesterol/phospholipid:diacylglycerol acyltransferase / Lecithin:cholesterol acyltransferase / Apolipoprotein A/E / : / Apolipoprotein A1/A4/E domain / Lipases, serine active site. / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
Apolipoprotein A-I / Phosphatidylcholine-sterol acyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 9.8 Å
AuthorsColeman B / Bedi S / Hill JH / Morris J / Manthei KA / Hart RC / He Y / Shah AS / Jerome WG / Vaisar T ...Coleman B / Bedi S / Hill JH / Morris J / Manthei KA / Hart RC / He Y / Shah AS / Jerome WG / Vaisar T / Bornfeldt KE / Song H / Segrest JP / Heinecke JW / Aller SG / Tesmer JJG / Davidson S
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)P01 HL116263 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01 HL153118 United States
CitationJournal: J Lipid Res / Year: 2025
Title: Lecithin:cholesterol acyltransferase binds a discontinuous binding site on adjacent apolipoprotein A-I belts in HDL.
Authors: Bethany Coleman / Shimpi Bedi / John H Hill / Jamie Morris / Kelly A Manthei / Rachel C Hart / Yi He / Amy S Shah / W Gray Jerome / Tomas Vaisar / Karin E Bornfeldt / Hyun Song / Jere P ...Authors: Bethany Coleman / Shimpi Bedi / John H Hill / Jamie Morris / Kelly A Manthei / Rachel C Hart / Yi He / Amy S Shah / W Gray Jerome / Tomas Vaisar / Karin E Bornfeldt / Hyun Song / Jere P Segrest / Jay W Heinecke / Stephen G Aller / John J G Tesmer / W Sean Davidson /
Abstract: Lecithin:cholesterol acyltransferase (LCAT) is a high-density lipoprotein (HDL) modifying protein that profoundly affects the composition and function of HDL subspecies. The cholesterol ...Lecithin:cholesterol acyltransferase (LCAT) is a high-density lipoprotein (HDL) modifying protein that profoundly affects the composition and function of HDL subspecies. The cholesterol esterification activity of LCAT is dramatically increased by apolipoprotein A-I (APOA1) on HDL, but the mechanism remains unclear. Using site-directed mutagenesis, cross-linking, mass spectrometry, electron microscopy, protein engineering, and molecular docking, we identified two LCAT binding sites formed by helices 4 and 6 from two antiparallel APOA1 molecules in HDL. Although the reciprocating APOA1 "belts" form two ostensibly symmetrical binding locations, LCAT can adopt distinct orientations at each site, as shown by our 9.8 Å cryoEM envelope. In one case, LCAT membrane binding domains align with the APOA1 belts and, in the other, the HDL phospholipids. By introducing disulfide bonds between the APOA1 helical domains, we demonstrated that LCAT does not require helical separation during its reaction cycle. This indicates that LCAT, anchored to APOA1 belts, accesses substrates and deposits products through interactions with the planar lipid surface. This model of the LCAT/APOA1 interaction provides insights into how LCAT and possibly other HDL-modifying factors engage the APOA1 scaffold, offering potential strategies to enhance LCAT activity in individuals with genetic defects.
History
DepositionJan 21, 2025-
Header (metadata) releaseApr 2, 2025-
Map releaseApr 2, 2025-
UpdateMay 7, 2025-
Current statusMay 7, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48724.png

Downloads & links

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Map

FileDownload / File: emd_48724.map.gz / Format: CCP4 / Size: 7.6 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.)
1.96 Å/pix.
x 126 pix.
= 246.96 Å		1.96 Å/pix.
x 126 pix.
= 246.96 Å		1.96 Å/pix.
x 126 pix.
= 246.96 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.96 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.23307376 - 1.5987242
Average (Standard dev.)-0.0054139285 (±0.07859828)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions126126126
Spacing126126126
CellA=B=C: 246.96 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_48724_half_map_1.map
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_48724_half_map_2.map
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Sample components

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Entire : Complex of 2 Lecithin:Cholesterol Acyltransferase molecules bound...

EntireName: Complex of 2 Lecithin:Cholesterol Acyltransferase molecules bound to Apolipoprotein dimer in HDL
Components
  • Complex: Complex of 2 Lecithin:Cholesterol Acyltransferase molecules bound to Apolipoprotein dimer in HDL
    • Protein or peptide: Phosphatidylcholine-sterol acyltransferase
  • Protein or peptide: Apolipoprotein A-I
  • Ligand: (4S,7R)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-3,5,8-TRIOXA-4-PHOSPHAHEXACOSAN-1-AMINIUM 4-OXIDE

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Supramolecule #1: Complex of 2 Lecithin:Cholesterol Acyltransferase molecules bound...

SupramoleculeName: Complex of 2 Lecithin:Cholesterol Acyltransferase molecules bound to Apolipoprotein dimer in HDL
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Apolipoprotein A-I

MacromoleculeName: Apolipoprotein A-I / type: protein_or_peptide / ID: 1
Details: molecular dynamics simulation containing 2 molecules of apolipoprotein A-I and 100 POPC
Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.120637 KDa
Recombinant expressionOrganism: Escherichia coli BL21 (bacteria)
SequenceString: DEPPQSPWDR VKDLATVYVD VLKDSGRDYV SQFEGSALGK QLNLKLLDNW DSVTSTFSKL REQLGPVTQE FWDNLEKETE GLRQEMSKD LEEVKAKVQP YLDDFQKKWQ EEMELYRQKV EPLRAELQEG ARQKLHELQE KLSPLGEEMR DRARAHVDAL R THLAPYSD ...String:
DEPPQSPWDR VKDLATVYVD VLKDSGRDYV SQFEGSALGK QLNLKLLDNW DSVTSTFSKL REQLGPVTQE FWDNLEKETE GLRQEMSKD LEEVKAKVQP YLDDFQKKWQ EEMELYRQKV EPLRAELQEG ARQKLHELQE KLSPLGEEMR DRARAHVDAL R THLAPYSD ELRQRLAARL EALKENGGAR LAEYHAKATE HLSTLSEKAK PALEDLRQGL LPVLESFKVS FLSALEEYTK KL NTQ

UniProtKB: Apolipoprotein A-I

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Macromolecule #2: Phosphatidylcholine-sterol acyltransferase

MacromoleculeName: Phosphatidylcholine-sterol acyltransferase / type: protein_or_peptide / ID: 2
Details: 4XWG Lecithin:Cholesterol Acyltransferase crystal structure of closed conformation
Number of copies: 2 / Enantiomer: LEVO / EC number: phosphatidylcholine-sterol O-acyltransferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44.879988 KDa
Recombinant expressionOrganism: Human adenovirus 5
SequenceString: HTRPVILVPG YLGNQLEAKL DKPDVVNWMC YRKTEDFFTI WLDLNMFLPL GVDCWIDNTR VVYNRSSGLV SNAPGVQIRV PGFGKTYSV EYLDSSKLAG YLHTLVQNLV NNGYVRDETV RAAPYDWRLE PGQQEEYYRK LAGLVEEMHA AYGKPVFLIG H SLGCLHLL ...String:
HTRPVILVPG YLGNQLEAKL DKPDVVNWMC YRKTEDFFTI WLDLNMFLPL GVDCWIDNTR VVYNRSSGLV SNAPGVQIRV PGFGKTYSV EYLDSSKLAG YLHTLVQNLV NNGYVRDETV RAAPYDWRLE PGQQEEYYRK LAGLVEEMHA AYGKPVFLIG H SLGCLHLL YFLLRQPQAW KDRFIDGFIS LGAPWGGSIK PMLVLASGDN QGIPIMSSIK LKEEQRITTT SPWMFPSRMA WP EDHVFIS TPSFNYTGRD FQRFFADLHF EEGWYMWLQS RDLLAGLPAP GVEVYCLYGV GLPTPRTYIY DHGFPYTDPV GVL YEDGDD TVATRSTELC GLWQGRQPQP VHLLPLHGIQ HLNMVFSNLT LEHINAILLG AYRQGPPASP TASPEPPPPE

UniProtKB: Phosphatidylcholine-sterol acyltransferase

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Macromolecule #3: (4S,7R)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-...

MacromoleculeName: (4S,7R)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-3,5,8-TRIOXA-4-PHOSPHAHEXACOSAN-1-AMINIUM 4-OXIDE
type: ligand / ID: 3 / Number of copies: 158 / Formula: 6PL
Molecular weightTheoretical: 763.1 Da
Chemical component information

ChemComp-6PL:
(4S,7R)-4-HYDROXY-N,N,N-TRIMETHYL-9-OXO-7-[(PALMITOYLOXY)METHYL]-3,5,8-TRIOXA-4-PHOSPHAHEXACOSAN-1-AMINIUM 4-OXIDE / phospholipid*YM

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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: 8
GridModel: Quantifoil R2/2 / Material: COPPER / Mesh: 200 / Support film - Material: CARBON / Support film - topology: CONTINUOUS
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 46.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: OTHER
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.4 µm

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Image processing

CTF correctionType: PHASE FLIPPING ONLY
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 9.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 44391
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-9mxz:
Lecithin:Cholesterol Acyltransferase Bound to Apolipoprotein A-I dimer in HDL

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