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- PDB-7xbk: Structure and mechanism of a mitochondrial AAA+ disaggregase CLPB -

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Basic information

Entry
Database: PDB / ID: 7xbk
TitleStructure and mechanism of a mitochondrial AAA+ disaggregase CLPB
Components
  • Isoform 2 of Caseinolytic peptidase B protein homolog
  • Unknown peptide
KeywordsCHAPERONE / CLPB / AAA-ATPase
Function / homology
Function and homology information


granulocyte differentiation / RIG-I signaling pathway / ATP-dependent protein disaggregase activity / Hydrolases; Acting on acid anhydrides; In phosphorus-containing anhydrides / antiviral innate immune response / 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. / 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. / ankyrin repeats / Ankyrin repeat / ATPase, AAA-type, core / 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
ADENOSINE-5'-TRIPHOSPHATE / Mitochondrial disaggregase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / negative staining / cryo EM / 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, 2items
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, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 25, 2023Provider: repository / Type: Initial release
Revision 1.1Feb 22, 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
Revision 1.2Jun 26, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond / em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Isoform 2 of Caseinolytic peptidase B protein homolog
B: Isoform 2 of Caseinolytic peptidase B protein homolog
C: Isoform 2 of Caseinolytic peptidase B protein homolog
D: Isoform 2 of Caseinolytic peptidase B protein homolog
E: Isoform 2 of Caseinolytic peptidase B protein homolog
F: Isoform 2 of Caseinolytic peptidase B protein homolog
G: Isoform 2 of Caseinolytic peptidase B protein homolog
H: Isoform 2 of Caseinolytic peptidase B protein homolog
I: Isoform 2 of Caseinolytic peptidase B protein homolog
L: Unknown peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)685,81426
Polymers681,56210
Non-polymers4,25216
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Isoform 2 of Caseinolytic peptidase B protein homolog / Suppressor of potassium transport defect 3


Mass: 75566.336 Da / Num. of mol.: 9 / Mutation: E425Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CLPB, HSP78, SKD3 / Variant: Q9H078-2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9H078, Hydrolases; Acting on acid anhydrides; In phosphorus-containing anhydrides
#2: Protein/peptide Unknown peptide


Mass: 1464.797 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#3: Chemical
ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: CELL / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: CLPB / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 6.8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: YES / Vitrification applied: YES
EM stainingType: NEGATIVE / Material: Uranyl Acetare
VitrificationCryogen name: NITROGEN

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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: SPOT SCAN
Electron lensMode: DARK FIELD / Nominal defocus max: 1400 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.19.2_4158refinement
PHENIX1.19.2_4158refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 45907 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 36.08 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.004826184
ELECTRON MICROSCOPYf_angle_d0.819635244
ELECTRON MICROSCOPYf_chiral_restr0.05263860
ELECTRON MICROSCOPYf_plane_restr0.00664540
ELECTRON MICROSCOPYf_dihedral_angle_d6.43513458

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