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- PDB-8u39: Structure of Human Mitochondrial Chaperonin V72I mutant -

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Basic information

Entry
Database: PDB / ID: 8u39
TitleStructure of Human Mitochondrial Chaperonin V72I mutant
Components60 kDa heat shock protein, mitochondrial
KeywordsCHAPERONE / chaperonin / human mitochondrial mHsp60 / hereditary spastic paraplegia SPG13 / cryo-EM / molecular dynamic simulation
Function / homology
Function and homology information


coated vesicle / isotype switching to IgG isotypes / mitochondrial unfolded protein response / TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation / apolipoprotein A-I binding / lipopolysaccharide receptor complex / protein import into mitochondrial intermembrane space / high-density lipoprotein particle binding / migrasome / cysteine-type endopeptidase activator activity ...coated vesicle / isotype switching to IgG isotypes / mitochondrial unfolded protein response / TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation / apolipoprotein A-I binding / lipopolysaccharide receptor complex / protein import into mitochondrial intermembrane space / high-density lipoprotein particle binding / migrasome / cysteine-type endopeptidase activator activity / positive regulation of T cell mediated immune response to tumor cell / chaperonin ATPase / Mitochondrial protein import / positive regulation of macrophage activation / negative regulation of execution phase of apoptosis / cellular response to interleukin-7 / MyD88-dependent toll-like receptor signaling pathway / 'de novo' protein folding / biological process involved in interaction with symbiont / sperm plasma membrane / apoptotic mitochondrial changes / B cell activation / B cell proliferation / positive regulation of interferon-alpha production / positive regulation of interleukin-10 production / DNA replication origin binding / apolipoprotein binding / positive regulation of execution phase of apoptosis / response to unfolded protein / Mitochondrial unfolded protein response (UPRmt) / isomerase activity / chaperone-mediated protein complex assembly / sperm midpiece / clathrin-coated pit / positive regulation of interleukin-12 production / Mitochondrial protein degradation / response to cold / secretory granule / T cell activation / protein maturation / ATP-dependent protein folding chaperone / lipopolysaccharide binding / positive regulation of T cell activation / positive regulation of interleukin-6 production / positive regulation of type II interferon production / p53 binding / unfolded protein binding / protein folding / single-stranded DNA binding / double-stranded RNA binding / protein-folding chaperone binding / protein refolding / early endosome / mitochondrial inner membrane / protein stabilization / mitochondrial matrix / ubiquitin protein ligase binding / negative regulation of apoptotic process / enzyme binding / cell surface / ATP hydrolysis activity / protein-containing complex / mitochondrion / extracellular space / RNA binding / extracellular exosome / ATP binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Chaperonin Cpn60, conserved site / Chaperonins cpn60 signature. / Chaperonin Cpn60/GroEL / GroEL-like equatorial domain superfamily / TCP-1-like chaperonin intermediate domain superfamily / GroEL-like apical domain superfamily / TCP-1/cpn60 chaperonin family / Chaperonin Cpn60/GroEL/TCP-1 family
Similarity search - Domain/homology
60 kDa heat shock protein, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsChen, L. / Wang, J.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI173104 United States
CitationJournal: Structure / Year: 2024
Title: Cryo-EM structure and molecular dynamic simulations explain the enhanced stability and ATP activity of the pathological chaperonin mutant.
Authors: Aiza Syed / Jihang Zhai / Baolin Guo / Yuan Zhao / Joseph Che-Yen Wang / Lingling Chen /
Abstract: Chaperonins Hsp60s are required for cellular vitality by assisting protein folding in an ATP-dependent mechanism. Although conserved, the human mitochondrial mHsp60 exhibits molecular characteristics ...Chaperonins Hsp60s are required for cellular vitality by assisting protein folding in an ATP-dependent mechanism. Although conserved, the human mitochondrial mHsp60 exhibits molecular characteristics distinct from the E. coli GroEL, with different conformational assembly and higher subunit association dynamics, suggesting a different mechanism. We previously found that the pathological mutant mHsp60 exhibits enhanced subunit association stability and ATPase activity. To provide structural explanations for the V72I mutational effects, here we determined a cryo-EM structure of mHsp60. Our structural analysis combined with molecular dynamic simulations showed mHsp60 with increased inter-subunit interface, binding free energy, and dissociation force, all contributing to its enhanced subunit association stability. The gate to the nucleotide-binding (NB) site in mHsp60 mimicked the open conformation in the nucleotide-bound state with an additional open channel leading to the NB site, both promoting the mutant's ATPase activity. Our studies highlight the importance of mHsp60's characteristics in its biological function.
History
DepositionSep 7, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 14, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
G: 60 kDa heat shock protein, mitochondrial
A: 60 kDa heat shock protein, mitochondrial
B: 60 kDa heat shock protein, mitochondrial
C: 60 kDa heat shock protein, mitochondrial
D: 60 kDa heat shock protein, mitochondrial
E: 60 kDa heat shock protein, mitochondrial
F: 60 kDa heat shock protein, mitochondrial


Theoretical massNumber of molelcules
Total (without water)391,1267
Polymers391,1267
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
60 kDa heat shock protein, mitochondrial


Mass: 55875.164 Da / Num. of mol.: 7 / Fragment: UNP residues 27-550 / Mutation: V72I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HSPD1 / Production host: Escherichia coli (E. coli) / References: UniProt: P10809

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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: Human Mitochondrial Chaperonin V72I Mutant / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 60 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.5
SpecimenConc.: 7.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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: 2500 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 50 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 30 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2Leginonimage acquisition
4cryoSPARCCTF correction
7UCSF ChimeraX1.6model fitting
8ISOLDE1.6model fitting
9Coot0.9model fitting
11cryoSPARCinitial Euler assignment
12cryoSPARCfinal Euler assignment
14cryoSPARC3D reconstruction
15PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C7 (7 fold cyclic)
3D reconstructionResolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 532348 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 7L7S

7l7s


Accession code: 7L7S / Source name: PDB / Type: experimental model

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