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- EMDB-33104: Structure and mechanism of a mitochondrial AAA+ disaggregase CLPB -

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Basic information

Entry
Database: EMDB / ID: EMD-33104
TitleStructure and mechanism of a mitochondrial AAA+ disaggregase CLPB
Map data
Sample
  • Complex: CLPB
    • Protein or peptide: Isoform 2 of Caseinolytic peptidase B protein homolog
    • Protein or peptide: Unknown peptide
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION
Function / homology
Function and homology information


granulocyte differentiation / RIG-I signaling pathway / ATP-dependent protein disaggregase activity / antiviral innate immune response / Hydrolases; Acting on acid anhydrides; In phosphorus-containing anhydrides / mitochondrial intermembrane space / cellular response to heat / ATP hydrolysis activity / mitochondrion / ATP binding / cytoplasm
Similarity search - Function
ClpA/B family / Clp ATPase, C-terminal / AAA domain (Cdc48 subfamily) / C-terminal, D2-small domain, of ClpB protein / C-terminal, D2-small domain, of ClpB protein / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ATPase, AAA-type, core / ankyrin repeats ...ClpA/B family / Clp ATPase, C-terminal / AAA domain (Cdc48 subfamily) / C-terminal, D2-small domain, of ClpB protein / C-terminal, D2-small domain, of ClpB protein / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ATPase, AAA-type, core / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Mitochondrial disaggregase
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / negative staining / Resolution: 3.7 Å
AuthorsWu D / Liu Y / Dai Y / Wang G / Lu G / Chen Y / Li N / Lin J / Gao N
Funding support China, 2 items
OrganizationGrant numberCountry
National Science Foundation (NSF, China)31725007 China
National Science Foundation (NSF, China)31922036 China
CitationJournal: PLoS Biol / Year: 2023
Title: Comprehensive structural characterization of the human AAA+ disaggregase CLPB in the apo- and substrate-bound states reveals a unique mode of action driven by oligomerization.
Authors: Damu Wu / Yan Liu / Yuhao Dai / Guopeng Wang / Guoliang Lu / Yan Chen / Ningning Li / Jinzhong Lin / Ning Gao /
Abstract: The human AAA+ ATPase CLPB (SKD3) is a protein disaggregase in the mitochondrial intermembrane space (IMS) and functions to promote the solubilization of various mitochondrial proteins. Loss-of- ...The human AAA+ ATPase CLPB (SKD3) is a protein disaggregase in the mitochondrial intermembrane space (IMS) and functions to promote the solubilization of various mitochondrial proteins. Loss-of-function CLPB mutations are associated with a few human diseases with neutropenia and neurological disorders. Unlike canonical AAA+ proteins, CLPB contains a unique ankyrin repeat domain (ANK) at its N-terminus. How CLPB functions as a disaggregase and the role of its ANK domain are currently unclear. Herein, we report a comprehensive structural characterization of human CLPB in both the apo- and substrate-bound states. CLPB assembles into homo-tetradecamers in apo-state and is remodeled into homo-dodecamers upon substrate binding. Conserved pore-loops (PLs) on the ATPase domains form a spiral staircase to grip and translocate the substrate in a step-size of 2 amino acid residues. The ANK domain is not only responsible for maintaining the higher-order assembly but also essential for the disaggregase activity. Interactome analysis suggests that the ANK domain may directly interact with a variety of mitochondrial substrates. These results reveal unique properties of CLPB as a general disaggregase in mitochondria and highlight its potential as a target for the treatment of various mitochondria-related diseases.
History
DepositionMar 21, 2022-
Header (metadata) releaseJan 25, 2023-
Map releaseJan 25, 2023-
UpdateFeb 22, 2023-
Current statusFeb 22, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33104.png

Downloads & links

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Map

FileDownload / File: emd_33104.map.gz / Format: CCP4 / Size: 67 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.08 Å
Density
Contour LevelBy AUTHOR: 0.06
Minimum - Maximum-0.024222955 - 2.2678688
Average (Standard dev.)0.0025506122 (±0.036575887)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions260260260
Spacing260260260
CellA=B=C: 280.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_33104_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_33104_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : CLPB

EntireName: CLPB
Components
  • Complex: CLPB
    • Protein or peptide: Isoform 2 of Caseinolytic peptidase B protein homolog
    • Protein or peptide: Unknown peptide
  • Ligand: ADENOSINE-5'-TRIPHOSPHATE
  • Ligand: MAGNESIUM ION

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Supramolecule #1: CLPB

SupramoleculeName: CLPB / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Isoform 2 of Caseinolytic peptidase B protein homolog

MacromoleculeName: Isoform 2 of Caseinolytic peptidase B protein homolog / type: protein_or_peptide / ID: 1 / Number of copies: 9 / Enantiomer: LEVO
EC number: Hydrolases; Acting on acid anhydrides; In phosphorus-containing anhydrides
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 75.566336 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MLGSLVLRRK ALAPRLLLRL LRSPTLRGHG GASGRNVTTG SLGEPQWLRV ATGGRPGTSP ALFSGRGAAT GGRQGGRFDT KCLAAATWG RLPGPEETLP GQDSWNGVPS RAGLGMCALA AALVVHCYSK SPSNKDAALL EAARANNMQE VSRLLSEGAD V NAKHRLGW ...String:
MLGSLVLRRK ALAPRLLLRL LRSPTLRGHG GASGRNVTTG SLGEPQWLRV ATGGRPGTSP ALFSGRGAAT GGRQGGRFDT KCLAAATWG RLPGPEETLP GQDSWNGVPS RAGLGMCALA AALVVHCYSK SPSNKDAALL EAARANNMQE VSRLLSEGAD V NAKHRLGW TALMVAAINR NNSVVQVLLA AGADPNLGDD FSSVYKTAKE QGIHSLEVLI TREDDFNNRL NNRASFKGCT AL HYAVLAD DYRTVKELLD GGANPLQRNE MGHTPLDYAR EGEVMKLLRT SEAKYQEKQR KREAEERRRF PLEQRLKEHI IGQ ESAIAT VGAAIRRKEN GWYDEEHPLV FLFLGSSGIG KTELAKQTAK YMHKDAKKGF IRLDMSEFQE RHEVAKFIGS PPGY VGHEE GGQLTKKLKQ CPNAVVLFDQ VDKAHPDVLT IMLQLFDEGR LTDGKGKTID CKDAIFIMTS NVASDEIAQH ALQLR QEAL EMSRNRIAEN LGDVQISDKI TISKNFKENV IRPILKAHFR RDEFLGRINE IVYFLPFCHS ELIQLVNKEL NFWAKR AKQ RHNITLLWDR EVADVLVDGY NVHYGARSIK HEVERRVVNQ LAAAYEQDLL PGGCTLRITV EDSDKQLLKS PELPSPQ AE KRLPKLRLEI IDKDSKTRRL DIRAPLHPEK VCNTI

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Macromolecule #2: Unknown peptide

MacromoleculeName: Unknown peptide / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.464797 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)

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Macromolecule #3: ADENOSINE-5'-TRIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-TRIPHOSPHATE / type: ligand / ID: 3 / Number of copies: 8 / Formula: ATP
Molecular weightTheoretical: 507.181 Da
Chemical component information

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 8 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Experimental details

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Structure determination

Methodnegative staining, cryo EM
Processingsingle particle reconstruction
Aggregation statecell

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Sample preparation

BufferpH: 6.8
StainingType: NEGATIVE / Material: Uranyl Acetare
VitrificationCryogen name: NITROGEN

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: DARK FIELD / Nominal defocus max: 1.4000000000000001 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 45907

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