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- PDB-8d6v: Structure of the Mycobacterium tuberculosis 20S proteasome bound ... -

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Basic information

Entry
Database: PDB / ID: 8d6v
TitleStructure of the Mycobacterium tuberculosis 20S proteasome bound to the C-terminal GQYL motif of the ATP-bound Mpa ATPase
Components
  • Proteasome subunit alpha
  • Proteasome subunit beta
  • Proteasome-associated ATPase
KeywordsANTIMICROBIAL PROTEIN / Mpa / proteasome
Function / homology
Function and homology information


retrograde protein transport, ER to cytosol / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / polyubiquitin modification-dependent protein binding / proteasomal protein catabolic process / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / proteasome complex / modification-dependent protein catabolic process / ATP hydrolysis activity ...retrograde protein transport, ER to cytosol / proteasome endopeptidase complex / proteasome core complex, beta-subunit complex / polyubiquitin modification-dependent protein binding / proteasomal protein catabolic process / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / proteasome complex / modification-dependent protein catabolic process / ATP hydrolysis activity / ATP binding / cytoplasm / cytosol
Similarity search - Function
Proteasome ATPase / Proteasomal ATPase, N-terminal OB domain / Proteasomal ATPase OB N-terminal domain / Proteasome, alpha subunit, bacterial / Proteasome subunit beta, actinobacteria / Proteasomal ATPase OB C-terminal domain / Proteasomal ATPase OB C-terminal domain / Proteasome alpha-type subunit / Proteasome alpha-type subunit profile. / Proteasome B-type subunit ...Proteasome ATPase / Proteasomal ATPase, N-terminal OB domain / Proteasomal ATPase OB N-terminal domain / Proteasome, alpha subunit, bacterial / Proteasome subunit beta, actinobacteria / Proteasomal ATPase OB C-terminal domain / Proteasomal ATPase OB C-terminal domain / Proteasome alpha-type subunit / Proteasome alpha-type subunit profile. / Proteasome B-type subunit / Proteasome beta-type subunit profile. / Proteasome subunit / Proteasome, subunit alpha/beta / ATPase, AAA-type, conserved site / AAA-protein family signature. / Nucleophile aminohydrolases, N-terminal / ATPase family associated with various cellular activities (AAA) / ATPase, AAA-type, core / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Nucleic acid-binding, OB-fold / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Proteasome subunit beta / Proteasome-associated ATPase / Proteasome subunit alpha
Similarity search - Component
Biological speciesMycobacterium tuberculosis (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsXiao, X. / Li, H.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Library of Medicine (NIH/NLM)R01 United States
CitationJournal: mSphere / Year: 2022
Title: The β-Grasp Domain of Proteasomal ATPase Mpa Makes Critical Contacts with the Mycobacterium tuberculosis 20S Core Particle to Facilitate Degradation.
Authors: Xiansha Xiao / Xiang Feng / Jin Hee Yoo / Amanda Kovach / K Heran Darwin / Huilin Li /
Abstract: Mycobacterium tuberculosis possesses a Pup-proteasome system analogous to the eukaryotic ubiquitin-proteasome pathway. We have previously shown that the hexameric mycobacterial proteasome ATPase (Mpa) ...Mycobacterium tuberculosis possesses a Pup-proteasome system analogous to the eukaryotic ubiquitin-proteasome pathway. We have previously shown that the hexameric mycobacterial proteasome ATPase (Mpa) recruits pupylated protein substrates via interactions between amino-terminal coiled-coils in Mpa monomers and the degradation tag Pup. However, it is unclear how Mpa rings interact with a proteasome due to the presence of a carboxyl-terminal β-grasp domain unique to Mpa homologues that makes the interaction highly unstable. Here, we describe newly identified critical interactions between Mpa and 20S core proteasomes. Interestingly, the Mpa C-terminal GQYL motif binds the 20S core particle activation pocket differently than the same motif of the ATP-independent proteasome accessory factor PafE. We further found that the β-hairpin of the Mpa β-grasp domain interacts variably with the H0 helix on top of the 20S core particle via a series of ionic and hydrogen-bond interactions. Individually mutating several involved residues reduced Mpa-mediated protein degradation both and . The Pup-proteasome system in Mycobacterium tuberculosis is critical for this species to cause lethal infections in mice. Investigating the molecular mechanism of how the Mpa ATPase recruits and unfolds pupylated substrates to the 20S proteasomal core particle for degradation will be essential to fully understand how degradation is regulated, and the structural information we report may be useful for the development of new tuberculosis chemotherapies.
History
DepositionJun 6, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 3, 2022Provider: repository / Type: Initial release
Revision 1.1Sep 7, 2022Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 9, 2022Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.3Jun 12, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Proteasome subunit alpha
C: Proteasome subunit alpha
D: Proteasome subunit alpha
E: Proteasome subunit alpha
F: Proteasome subunit alpha
G: Proteasome subunit alpha
H: Proteasome subunit alpha
I: Proteasome subunit alpha
J: Proteasome subunit alpha
K: Proteasome subunit alpha
L: Proteasome subunit alpha
M: Proteasome subunit alpha
N: Proteasome subunit alpha
P: Proteasome subunit beta
Q: Proteasome subunit beta
R: Proteasome subunit beta
S: Proteasome subunit beta
T: Proteasome subunit beta
U: Proteasome subunit beta
V: Proteasome subunit beta
W: Proteasome subunit beta
X: Proteasome subunit beta
Y: Proteasome subunit beta
Z: Proteasome subunit beta
a: Proteasome subunit beta
b: Proteasome subunit beta
c: Proteasome subunit beta
d: Proteasome-associated ATPase
e: Proteasome-associated ATPase
f: Proteasome-associated ATPase
g: Proteasome-associated ATPase
h: Proteasome-associated ATPase
i: Proteasome-associated ATPase
j: Proteasome-associated ATPase
O: Proteasome subunit alpha


Theoretical massNumber of molelcules
Total (without water)804,75935
Polymers804,75935
Non-polymers00
Water00
1


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

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Components

#1: Protein
Proteasome subunit alpha / 20S proteasome alpha subunit / Proteasome core protein PrcA


Mass: 26911.039 Da / Num. of mol.: 14
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: prcA, MRA_2124 / Production host: Escherichia coli (E. coli)
References: UniProt: A5U4D5, proteasome endopeptidase complex
#2: Protein
Proteasome subunit beta / 20S proteasome beta subunit / Proteasome core protein PrcB


Mass: 30332.006 Da / Num. of mol.: 14
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria)
Gene: prcB, E5M05_20980, E5M23_20030, E5M52_20895, E5M78_20920, ERS007665_00482, ERS007670_00434, ERS007679_01035, ERS007683_02087, ERS007720_00612, ERS007722_01880, ERS007741_02624, ERS024276_00650, SAMEA2683035_00452
Production host: Escherichia coli (E. coli)
References: UniProt: A0A045HFG5, proteasome endopeptidase complex
#3: Protein/peptide
Proteasome-associated ATPase / AAA ATPase forming ring-shaped complexes / ARC / Mycobacterial proteasome ATPase


Mass: 479.527 Da / Num. of mol.: 7 / Fragment: C-terminal Gly-Gln-Tyr-Leu (GQYL) motif
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mycobacterium tuberculosis (bacteria) / Gene: mpa, BCG_2132c / Production host: Escherichia coli (E. coli) / References: UniProt: A1KKF8

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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: binary complex of 20S proteasome with ATPase Mpa / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Mycobacterium tuberculosis (bacteria)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R2/1
VitrificationInstrument: FEI VITROBOT MARK II / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 283.15 K

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 5000 nm / Nominal defocus min: 1200 nm
Specimen holderCryogen: NITROGEN
Image recordingAverage exposure time: 6 sec. / Electron dose: 1.2 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)
Image scansMovie frames/image: 30

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 213000 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00347066
ELECTRON MICROSCOPYf_angle_d0.49463704
ELECTRON MICROSCOPYf_dihedral_angle_d3.7596853
ELECTRON MICROSCOPYf_chiral_restr0.0437251
ELECTRON MICROSCOPYf_plane_restr0.0048400

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