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- EMDB-26595: CryoEM structure of human LACTB filament -

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Basic information

Entry
Database: EMDB / ID: EMD-26595
TitleCryoEM structure of human LACTB filament
Map dataRefine3D map
Sample
  • Complex: LACTB
    • Protein or peptide: Serine beta-lactamase-like protein LACTB, mitochondrial
Keywordsserine protease / filament / tumor suppressor / membrane / mitochondria / beta lactamase / MEMBRANE PROTEIN
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)
Methodhelical reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsBennett JA / Steward LR / Aydin H
Funding support United States, 1 items
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, 2022-
Header (metadata) releaseDec 7, 2022-
Map releaseDec 7, 2022-
UpdateJun 12, 2024-
Current statusJun 12, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26595.png

Downloads & links

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Map

FileDownload / File: emd_26595.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationRefine3D map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 320 pix.
= 262.752 Å		0.82 Å/pix.
x 320 pix.
= 262.752 Å		0.82 Å/pix.
x 320 pix.
= 262.752 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.8211 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0042
Minimum - Maximum-0.012025551 - 0.023476535
Average (Standard dev.)0.000008085424 (±0.0010279961)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 262.752 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_26595_msk_1.map
Projections & Slices
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Additional map: Postprocess map

Fileemd_26595_additional_1.map
AnnotationPostprocess map
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Half map: Refine3D half map 1

Fileemd_26595_half_map_1.map
AnnotationRefine3D half map 1
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AxesZYX

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Half map: Refine3D half map 2

Fileemd_26595_half_map_2.map
AnnotationRefine3D half map 2
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Sample components

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Entire : LACTB

EntireName: LACTB
Components
  • Complex: LACTB
    • Protein or peptide: Serine beta-lactamase-like protein LACTB, mitochondrial

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Supramolecule #1: LACTB

SupramoleculeName: LACTB / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: Uniprot ID: P83111 - HUMAN LACTB, Serine beta-lactamase-like protein LACTB, mitochondrial
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 510 KDa

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

MacromoleculeName: Serine beta-lactamase-like protein LACTB, mitochondrial
type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO / EC number: Hydrolases; Acting on peptide bonds (peptidases)
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 51.318648 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: APPCSRCFAR AIESSRDLLH RIKDEVGAPG IVVGVSVDGK EVWSEGLGYA DVENRVPCKP ETVMRIASIS KSLTMVALAK LWEAGKLDL DIPVQHYVPE FPEKEYEGEK VSVTTRLLIS HLSGIRHYEK DIKKVKEEKA YKALKMMKEN VAFEQEKEGK S NEKNDFTK ...String:
APPCSRCFAR AIESSRDLLH RIKDEVGAPG IVVGVSVDGK EVWSEGLGYA DVENRVPCKP ETVMRIASIS KSLTMVALAK LWEAGKLDL DIPVQHYVPE FPEKEYEGEK VSVTTRLLIS HLSGIRHYEK DIKKVKEEKA YKALKMMKEN VAFEQEKEGK S NEKNDFTK FKTEQENEAK CRNSKPGKKK NDFEQGELYL REKFENSIES LRLFKNDPLF FKPGSQFLYS TFGYTLLAAI VE RASGCKY LDYMQKIFHD LDMLTTVQEE NEPVIYNRAR FYVYNKKKRL VNTPYVDNSY KWAGGGFLST VGDLLKFGNA MLY GYQVGL FKNSNENLLP GYLKPETMVM MWTPVPNTEM SWDKEGKYAM AWGVVERKQT YGSCRKQRHY ASHTGGAVGA SSVL LVLPE ELDTETINNK VPPRGIIVSI ICNMQSVGLN STALKIALEF DKDRSD

UniProtKB: Serine beta-lactamase-like protein LACTB, mitochondrial

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration0.3 mg/mL
BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average exposure time: 3.985 sec. / Average electron dose: 59.58 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 21.582 Å
Applied symmetry - Helical parameters - Δ&Phi: -48.258 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.1) / Number images used: 248548
Startup modelType of model: OTHER / Details: Featureless cylinder
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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