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- PDB-9mxz: Lecithin:Cholesterol Acyltransferase Bound to Apolipoprotein A-I ... -

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Basic information

Entry
Database: PDB / ID: 9mxz
TitleLecithin:Cholesterol Acyltransferase Bound to Apolipoprotein A-I dimer in HDL
Components
  • Apolipoprotein A-I
  • Phosphatidylcholine-sterol acyltransferase
KeywordsLIPID TRANSPORT / Complex / Lecithin:Cholesterol Acyltransferase / Apolipoprotein A-I / HDL
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 / 1-alkyl-2-acetylglycerophosphocholine esterase activity / negative regulation of response to cytokine stimulus / protein oxidation / vitamin transport / apolipoprotein A-I binding / cholesterol import / negative regulation of heterotypic cell-cell adhesion / Scavenging by Class B Receptors / apolipoprotein A-I receptor binding / phosphatidylcholine metabolic process / negative regulation of cell adhesion molecule production / apolipoprotein receptor binding / ABC transporters in lipid homeostasis / negative regulation of cytokine production involved in immune response / HDL assembly / high-density lipoprotein particle binding / phosphatidylcholine biosynthetic process / negative regulation of very-low-density lipoprotein particle remodeling / very-low-density lipoprotein particle remodeling / acylglycerol homeostasis / phosphatidylcholine-sterol O-acyltransferase activator activity / cholesterol transport / positive regulation of phospholipid efflux / Chylomicron remodeling / lipoprotein metabolic process / cellular response to lipoprotein particle stimulus / phospholipid homeostasis / Chylomicron assembly / high-density lipoprotein particle clearance / phospholipid efflux / chylomicron / high-density lipoprotein particle remodeling / reverse cholesterol transport / positive regulation of cholesterol metabolic process / high-density lipoprotein particle assembly / chemorepellent activity / cholesterol transfer activity / low-density lipoprotein particle / high-density lipoprotein particle / very-low-density lipoprotein particle / cholesterol efflux / regulation of Cdc42 protein signal transduction / HDL remodeling / A2-type glycerophospholipase activity / triglyceride homeostasis / negative chemotaxis / Scavenging by Class A Receptors / negative regulation of interleukin-1 beta production / response to copper ion / cholesterol binding / amyloid-beta formation / positive regulation of Rho protein signal transduction / phospholipid metabolic process / positive regulation of cholesterol efflux / positive regulation of substrate adhesion-dependent cell spreading / endocytic vesicle / positive regulation of stress fiber assembly / cholesterol metabolic process / negative regulation of tumor necrosis factor-mediated signaling pathway / Scavenging of heme from plasma / Retinoid metabolism and transport / Dengue virus activates/modulates innate and adaptive immune responses / heat shock protein binding / endocytic vesicle lumen / cholesterol homeostasis / positive regulation of phagocytosis / response to glucocorticoid / integrin-mediated signaling pathway / lipid metabolic process / Post-translational protein phosphorylation / Heme signaling / Maturation of DENV proteins / PPARA activates gene expression / negative regulation of inflammatory response / phospholipid binding / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / Platelet degranulation / amyloid-beta binding / extracellular vesicle / Dengue Virus-Host Interactions / cytoplasmic vesicle / secretory granule lumen / blood microparticle / early endosome / protein stabilization / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / receptor ligand activity / Amyloid fiber formation
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
Chem-6PL / Apolipoprotein A-I / Phosphatidylcholine-sterol acyltransferase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 9.8 Å
AuthorsColeman, B. / Bedi, S. / Hill, J.H. / Morris, J. / Manthei, K.A. / Hart, R.C. / He, Y. / Shah, A.S. / Jerome, W.G. / Vaisar, T. ...Coleman, B. / Bedi, S. / Hill, J.H. / Morris, J. / Manthei, K.A. / Hart, R.C. / He, Y. / Shah, A.S. / Jerome, W.G. / Vaisar, T. / Bornfeldt, K.E. / Song, H. / Segrest, J.P. / Heinecke, J.W. / Aller, S.G. / Tesmer, J.J.G. / Davidson, S.
Funding support United States, 2items
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, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 2, 2025Provider: repository / Type: Initial release
Revision 1.0Apr 2, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 2, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 2, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 2, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 2, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Apr 9, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
E: Apolipoprotein A-I
A: Apolipoprotein A-I
B: Phosphatidylcholine-sterol acyltransferase
C: Phosphatidylcholine-sterol acyltransferase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)266,571162
Polymers146,0014
Non-polymers120,570158
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 Apolipoprotein A-I / Apo-AI / ApoA-I / Apolipoprotein A1


Mass: 28120.637 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: molecular dynamics simulation containing 2 molecules of apolipoprotein A-I and 100 POPC
Source: (gene. exp.) Homo sapiens (human) / Gene: APOA1 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: P02647
#2: Protein Phosphatidylcholine-sterol acyltransferase / 1-alkyl-2-acetylglycerophosphocholine esterase / Lecithin-cholesterol acyltransferase / ...1-alkyl-2-acetylglycerophosphocholine esterase / Lecithin-cholesterol acyltransferase / Phospholipid-cholesterol acyltransferase / Platelet-activating factor acetylhydrolase / PAF acetylhydrolase


Mass: 44879.988 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: 4XWG Lecithin:Cholesterol Acyltransferase crystal structure of closed conformation
Source: (gene. exp.) Homo sapiens (human) / Gene: LCAT / Production host: Human adenovirus 5
References: UniProt: P04180, phosphatidylcholine-sterol O-acyltransferase, 1-alkyl-2-acetylglycerophosphocholine esterase
#3: Chemical...
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 / 1-PALMITOYL-2-STEAROYL-SN-GLYCERO-3-PHOSPHOCHOLINE


Mass: 763.100 Da / Num. of mol.: 158 / Source method: obtained synthetically / Formula: C42H85NO8P / Comment: phospholipid*YM
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: Complex of 2 Lecithin:Cholesterol Acyltransferase molecules bound to Apolipoprotein dimer in HDL
Type: COMPLEX / Entity ID: #2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21 (bacteria)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

MicroscopyModel: TFS GLACIOS
Electron gunElectron source: OTHER / Accelerating voltage: 200 kV / Illumination mode: OTHER
Electron lensMode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 400 nm
Image recordingElectron dose: 46 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM softwareName: HADDOCK / Category: model fitting
CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 9.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 44391 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT

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