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- PDB-8erl: CryoEM Structure of Lipoprotein Lipase Dimer -

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Basic information

Entry
Database: PDB / ID: 8erl
TitleCryoEM Structure of Lipoprotein Lipase Dimer
ComponentsLipoprotein lipase
KeywordsHYDROLASE / Dimer / lipase
Function / homology
Function and homology information


Assembly of active LPL and LIPC lipase complexes / positive regulation of chemokine production => GO:0032722 / lipoprotein lipase / lipoprotein lipase activity / positive regulation of tumor necrosis factor production => GO:0032760 / positive regulation of sequestering of triglyceride / low-density lipoprotein particle mediated signaling / chylomicron remodeling / positive regulation of cholesterol storage / phospholipase A1 ...Assembly of active LPL and LIPC lipase complexes / positive regulation of chemokine production => GO:0032722 / lipoprotein lipase / lipoprotein lipase activity / positive regulation of tumor necrosis factor production => GO:0032760 / positive regulation of sequestering of triglyceride / low-density lipoprotein particle mediated signaling / chylomicron remodeling / positive regulation of cholesterol storage / phospholipase A1 / phosphatidylserine 1-acylhydrolase activity / 1-acyl-2-lysophosphatidylserine acylhydrolase activity / phospholipase A1 activity / triglyceride catabolic process / phospholipase activity / lipase activity / very-low-density lipoprotein particle remodeling / positive regulation of macrophage derived foam cell differentiation / cellular response to nutrient / chylomicron / very-low-density lipoprotein particle / triacylglycerol lipase activity / heparan sulfate proteoglycan binding / positive regulation of chemokine (C-X-C motif) ligand 2 production / triglyceride homeostasis / cellular response to fatty acid / triglyceride metabolic process / lipoprotein particle binding / apolipoprotein binding / positive regulation of fat cell differentiation / phospholipid metabolic process / response to glucose / lipid catabolic process / positive regulation of interleukin-1 beta production / cholesterol homeostasis / response to bacterium / fatty acid biosynthetic process / positive regulation of inflammatory response / positive regulation of interleukin-6 production / heparin binding / signaling receptor binding / calcium ion binding / cell surface / protein homodimerization activity / extracellular space / plasma membrane
Similarity search - Function
Lipoprotein lipase / Lipase, LIPH-type / Lipase, N-terminal / Triacylglycerol lipase family / Lipase / Lipase / Lipoxygenase homology 2 (beta barrel) domain / PLAT/LH2 domain / PLAT/LH2 domain superfamily / PLAT/LH2 domain ...Lipoprotein lipase / Lipase, LIPH-type / Lipase, N-terminal / Triacylglycerol lipase family / Lipase / Lipase / Lipoxygenase homology 2 (beta barrel) domain / PLAT/LH2 domain / PLAT/LH2 domain superfamily / PLAT/LH2 domain / PLAT domain profile. / Lipases, serine active site. / Alpha/Beta hydrolase fold
Similarity search - Domain/homology
Biological speciesBos taurus (cattle)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.9 Å
AuthorsGunn, K.H. / Neher, S.B.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)R01HL125654 United States
American Heart Association900354 United States
CitationJournal: Nat Commun / Year: 2023
Title: Structure of dimeric lipoprotein lipase reveals a pore adjacent to the active site.
Authors: Kathryn H Gunn / Saskia B Neher /
Abstract: Lipoprotein lipase (LPL) hydrolyzes triglycerides from circulating lipoproteins, releasing free fatty acids. Active LPL is needed to prevent hypertriglyceridemia, which is a risk factor for ...Lipoprotein lipase (LPL) hydrolyzes triglycerides from circulating lipoproteins, releasing free fatty acids. Active LPL is needed to prevent hypertriglyceridemia, which is a risk factor for cardiovascular disease (CVD). Using cryogenic electron microscopy (cryoEM), we determined the structure of an active LPL dimer at 3.9 Å resolution. This structure reveals an open hydrophobic pore adjacent to the active site residues. Using modeling, we demonstrate that this pore can accommodate an acyl chain from a triglyceride. Known LPL mutations that lead to hypertriglyceridemia localize to the end of the pore and cause defective substrate hydrolysis. The pore may provide additional substrate specificity and/or allow unidirectional acyl chain release from LPL. This structure also revises previous models on how LPL dimerizes, revealing a C-terminal to C-terminal interface. We hypothesize that this active C-terminal to C-terminal conformation is adopted by LPL when associated with lipoproteins in capillaries.
History
DepositionOct 12, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2023Provider: repository / Type: Initial release
Revision 1.1May 17, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Lipoprotein lipase
B: Lipoprotein lipase


Theoretical massNumber of molelcules
Total (without water)106,8982
Polymers106,8982
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, cross-linking
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Lipoprotein lipase / LPL


Mass: 53448.789 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (cattle) / References: UniProt: P11151, lipoprotein lipase

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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: Lipoprotein Lipase Dimer / Type: COMPLEX / Entity ID: all / Source: NATURAL
Molecular weightValue: 0.101 MDa / Experimental value: NO
Source (natural)Organism: Bos taurus (cattle)
Buffer solutionpH: 8
SpecimenConc.: 0.55 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil
VitrificationCryogen name: ETHANE-PROPANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 55.1 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameCategory
1cryoSPARCparticle selection
10cryoSPARCinitial Euler assignment
11cryoSPARCfinal Euler assignment
CTF correctionType: NONE
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 527205 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0056776
ELECTRON MICROSCOPYf_angle_d1.2779176
ELECTRON MICROSCOPYf_dihedral_angle_d15.422466
ELECTRON MICROSCOPYf_chiral_restr0.065980
ELECTRON MICROSCOPYf_plane_restr0.0061174

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