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- PDB-7ulw: CryoEM structure of human LACTB filament -

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Basic information

Entry
Database: PDB / ID: 7ulw
TitleCryoEM structure of human LACTB filament
ComponentsSerine beta-lactamase-like protein LACTB, mitochondrial
KeywordsMEMBRANE PROTEIN / serine protease / filament / tumor suppressor / membrane / mitochondria / beta lactamase
Function / homology
Function and homology information


Hydrolases; Acting on peptide bonds (peptidases) / regulation of lipid metabolic process / lipid metabolic process / peptidase activity / mitochondrion / proteolysis / identical protein binding / cytosol
Similarity search - Function
: / Beta-lactamase-related / Beta-lactamase / Beta-lactamase/transpeptidase-like
Similarity search - Domain/homology
Serine beta-lactamase-like protein LACTB, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsBennett, J.A. / Steward, L.R. / Aydin, H.
Funding support United States, 1items
OrganizationGrant numberCountry
Other government United States
CitationJournal: PLoS Biol / Year: 2022
Title: The structure of the human LACTB filament reveals the mechanisms of assembly and membrane binding.
Authors: Jeremy A Bennett / Lottie R Steward / Johannes Rudolph / Adam P Voss / Halil Aydin /
Abstract: Mitochondria are complex organelles that play a central role in metabolism. Dynamic membrane-associated processes regulate mitochondrial morphology and bioenergetics in response to cellular demand. ...Mitochondria are complex organelles that play a central role in metabolism. Dynamic membrane-associated processes regulate mitochondrial morphology and bioenergetics in response to cellular demand. In tumor cells, metabolic reprogramming requires active mitochondrial metabolism for providing key metabolites and building blocks for tumor growth and rapid proliferation. To counter this, the mitochondrial serine beta-lactamase-like protein (LACTB) alters mitochondrial lipid metabolism and potently inhibits the proliferation of a variety of tumor cells. Mammalian LACTB is localized in the mitochondrial intermembrane space (IMS), where it assembles into filaments to regulate the efficiency of essential metabolic processes. However, the structural basis of LACTB polymerization and regulation remains incompletely understood. Here, we describe how human LACTB self-assembles into micron-scale filaments that increase their catalytic activity. The electron cryo-microscopy (cryoEM) structure defines the mechanism of assembly and reveals how highly ordered filament bundles stabilize the active state of the enzyme. We identify and characterize residues that are located at the filament-forming interface and further show that mutations that disrupt filamentation reduce enzyme activity. Furthermore, our results provide evidence that LACTB filaments can bind lipid membranes. These data reveal the detailed molecular organization and polymerization-based regulation of human LACTB and provide new insights into the mechanism of mitochondrial membrane organization that modulates lipid metabolism.
History
DepositionApr 5, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 7, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 4, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 11, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Jun 12, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Serine beta-lactamase-like protein LACTB, mitochondrial
B: Serine beta-lactamase-like protein LACTB, mitochondrial
C: Serine beta-lactamase-like protein LACTB, mitochondrial
D: Serine beta-lactamase-like protein LACTB, mitochondrial
E: Serine beta-lactamase-like protein LACTB, mitochondrial
F: Serine beta-lactamase-like protein LACTB, mitochondrial


Theoretical massNumber of molelcules
Total (without water)307,9126
Polymers307,9126
Non-polymers00
Water00
1


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

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Components

#1: Protein
Serine beta-lactamase-like protein LACTB, mitochondrial


Mass: 51318.648 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LACTB, MRPL56, UNQ843/PRO1781 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: P83111, Hydrolases; Acting on peptide bonds (peptidases)

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: LACTB / Type: COMPLEX
Details: Uniprot ID: P83111 - HUMAN LACTB, Serine beta-lactamase-like protein LACTB, mitochondrial
Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.51 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli BL21(DE3) (bacteria)
Buffer solutionpH: 7.5
SpecimenConc.: 0.3 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
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: 1500 nm / Nominal defocus min: 500 nm
Image recordingAverage exposure time: 3.985 sec. / Electron dose: 59.58 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM software
IDNameVersionCategory
2SerialEMimage acquisition
13RELION3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -48.258 ° / Axial rise/subunit: 21.582 Å / Axial symmetry: C1
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 248548 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00219185
ELECTRON MICROSCOPYf_angle_d0.40625976
ELECTRON MICROSCOPYf_dihedral_angle_d13.4717050
ELECTRON MICROSCOPYf_chiral_restr0.0392883
ELECTRON MICROSCOPYf_plane_restr0.0033292

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