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- PDB-7us2: PARL-cleaved Skd3 (human ClpB) E455Q Nucleotide Binding Domain he... -

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Basic information

Entry
Database: PDB / ID: 7us2
TitlePARL-cleaved Skd3 (human ClpB) E455Q Nucleotide Binding Domain hexamer bound to ATPgammaS, open conformation
Components
  • Caseinolytic peptidase B protein homolog
  • Substrate
KeywordsCHAPERONE / AAA+ ATPase / Mitochondria / Protein Folding
Function / homology
Function and homology information


RIG-I signaling pathway / granulocyte differentiation / 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 / C-terminal, D2-small domain, of ClpB protein / C-terminal, D2-small domain, of ClpB protein / AAA domain (Cdc48 subfamily) / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats ...: / ClpA/B family / Clp ATPase, C-terminal / C-terminal, D2-small domain, of ClpB protein / C-terminal, D2-small domain, of ClpB protein / AAA domain (Cdc48 subfamily) / Ankyrin repeats (3 copies) / Ankyrin repeat profile. / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / ATPase, AAA-type, core / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / Mitochondrial disaggregase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.76 Å
AuthorsGupta, A. / Lentzsch, A.M. / Siegel, A.S. / Yu, Z. / Lu, C. / Chio, U.S. / Cheng, Y. / Shan, S.-o.
Funding support United States, 6items
OrganizationGrant numberCountry
National Institutes of Health/Office of the DirectorOD021741 United States
National Institutes of Health/Office of the DirectorOD026881 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM129541 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM136321 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM137463 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM140847 United States
CitationJournal: Sci Adv / Year: 2023
Title: Dodecamer assembly of a metazoan AAA chaperone couples substrate extraction to refolding.
Authors: Arpit Gupta / Alfred M Lentzsch / Alex Siegel / Zanlin Yu / Un Seng Chio / Yifan Cheng / Shu-Ou Shan /
Abstract: Ring-forming AAA chaperones solubilize protein aggregates and protect organisms from proteostatic stress. In metazoans, the AAA chaperone Skd3 in the mitochondrial intermembrane space (IMS) is ...Ring-forming AAA chaperones solubilize protein aggregates and protect organisms from proteostatic stress. In metazoans, the AAA chaperone Skd3 in the mitochondrial intermembrane space (IMS) is critical for human health and efficiently refolds aggregated proteins, but its underlying mechanism is poorly understood. Here, we show that Skd3 harbors both disaggregase and protein refolding activities enabled by distinct assembly states. High-resolution structures of Skd3 hexamers in distinct conformations capture ratchet-like motions that mediate substrate extraction. Unlike previously described disaggregases, Skd3 hexamers further assemble into dodecameric cages in which solubilized substrate proteins can attain near-native states. Skd3 mutants defective in dodecamer assembly retain disaggregase activity but are impaired in client refolding, linking the disaggregase and refolding activities to the hexameric and dodecameric states of Skd3, respectively. We suggest that Skd3 is a combined disaggregase and foldase, and this property is particularly suited to meet the complex proteostatic demands in the mitochondrial IMS.
History
DepositionApr 22, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 8, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Caseinolytic peptidase B protein homolog
B: Caseinolytic peptidase B protein homolog
C: Caseinolytic peptidase B protein homolog
D: Caseinolytic peptidase B protein homolog
E: Caseinolytic peptidase B protein homolog
F: Caseinolytic peptidase B protein homolog
P: Substrate
hetero molecules


Theoretical massNumber of molelcules
Total (without water)399,97219
Polymers396,6877
Non-polymers3,28512
Water00
1


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

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Components

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


Mass: 65912.883 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CLPB, HSP78, SKD3 / Production host: Escherichia coli (E. coli)
References: UniProt: Q9H078, Hydrolases; Acting on acid anhydrides; In phosphorus-containing anhydrides
#2: Protein/peptide Substrate


Mass: 1209.482 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-AGS / PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-GAMMA-S / ADENOSINE 5'-(3-THIOTRIPHOSPHATE) / ADENOSINE 5'-(GAMMA-THIOTRIPHOSPHATE) / ADENOSINE-5'-DIPHOSPHATE MONOTHIOPHOSPHATE


Mass: 523.247 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C10H16N5O12P3S / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP-gamma-S, energy-carrying molecule analogue*YM
#4: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 6 / 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: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: PARL-cleaved Skd3 / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.397 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenConc.: 0.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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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: -2000 nm / Nominal defocus min: -1000 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1459443 / Symmetry type: POINT

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