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- EMDB-12316: D1-state of wild type human mitochondrial LONP1 protease -

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Basic information

Entry
Database: EMDB / ID: EMD-12316
TitleD1-state of wild type human mitochondrial LONP1 protease
Map data
Sample
  • Complex: D1-state of LonP1 hexameric complex
    • Protein or peptide: Lon protease homolog, mitochondrial
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
Function / homology
Function and homology information


oxidation-dependent protein catabolic process / PH domain binding / endopeptidase La / G-quadruplex DNA binding / response to aluminum ion / mitochondrial DNA metabolic process / mitochondrial genome maintenance / ATP-dependent peptidase activity / protein quality control for misfolded or incompletely synthesized proteins / mitochondrial nucleoid ...oxidation-dependent protein catabolic process / PH domain binding / endopeptidase La / G-quadruplex DNA binding / response to aluminum ion / mitochondrial DNA metabolic process / mitochondrial genome maintenance / ATP-dependent peptidase activity / protein quality control for misfolded or incompletely synthesized proteins / mitochondrial nucleoid / insulin receptor substrate binding / chaperone-mediated protein complex assembly / DNA polymerase binding / regulation of peptidyl-tyrosine phosphorylation / negative regulation of insulin receptor signaling pathway / mitochondrion organization / response to hormone / proteolysis involved in protein catabolic process / ADP binding / protein catabolic process / single-stranded DNA binding / cellular response to oxidative stress / sequence-specific DNA binding / single-stranded RNA binding / response to hypoxia / mitochondrial matrix / serine-type endopeptidase activity / ATP hydrolysis activity / mitochondrion / nucleoplasm / ATP binding / membrane / identical protein binding / cytosol
Similarity search - Function
Lon protease homologue, chloroplastic/mitochondrial / Lon protease, bacterial/eukaryotic-type / Peptidase S16, active site / ATP-dependent serine proteases, lon family, serine active site. / Lon proteolytic domain profile. / Peptidase S16, Lon proteolytic domain / Lon protease / Lon protease (S16) C-terminal proteolytic domain / Lon protease, N-terminal domain superfamily / Lon N-terminal domain profile. ...Lon protease homologue, chloroplastic/mitochondrial / Lon protease, bacterial/eukaryotic-type / Peptidase S16, active site / ATP-dependent serine proteases, lon family, serine active site. / Lon proteolytic domain profile. / Peptidase S16, Lon proteolytic domain / Lon protease / Lon protease (S16) C-terminal proteolytic domain / Lon protease, N-terminal domain superfamily / Lon N-terminal domain profile. / Lon protease, N-terminal domain / ATP-dependent protease La (LON) substrate-binding domain / Found in ATP-dependent protease La (LON) / PUA-like superfamily / ATPase family associated with various cellular activities (AAA) / ATPase, AAA-type, core / Ribosomal protein S5 domain 2-type fold, subgroup / Ribosomal protein S5 domain 2-type fold / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Lon protease homolog, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 15.0 Å
AuthorsMohammed I / Schmitz KA / Schenck N / Maier T / Abrahams JP
CitationJournal: Structure / Year: 2022
Title: Catalytic cycling of human mitochondrial Lon protease.
Authors: Inayathulla Mohammed / Kai A Schmitz / Niko Schenck / Dimitrios Balasopoulos / Annika Topitsch / Timm Maier / Jan Pieter Abrahams /
Abstract: The mitochondrial Lon protease (LonP1) regulates mitochondrial health by removing redundant proteins from the mitochondrial matrix. We determined LonP1 in eight nucleotide-dependent conformational ...The mitochondrial Lon protease (LonP1) regulates mitochondrial health by removing redundant proteins from the mitochondrial matrix. We determined LonP1 in eight nucleotide-dependent conformational states by cryoelectron microscopy (cryo-EM). The flexible assembly of N-terminal domains had 3-fold symmetry, and its orientation depended on the conformational state. We show that a conserved structural motif around T803 with a high similarity to the trypsin catalytic triad is essential for proteolysis. We show that LonP1 is not regulated by redox potential, despite the presence of two conserved cysteines at disulfide-bonding distance in its unfoldase core. Our data indicate how sequential ATP hydrolysis controls substrate protein translocation in a 6-fold binding change mechanism. Substrate protein translocation, rather than ATP hydrolysis, is a rate-limiting step, suggesting that LonP1 is a Brownian ratchet with ATP hydrolysis preventing translocation reversal. 3-fold rocking motions of the flexible N-domain assembly may assist thermal unfolding of the substrate protein.
History
DepositionFeb 9, 2021-
Header (metadata) releaseApr 28, 2021-
Map releaseApr 28, 2021-
UpdateNov 9, 2022-
Current statusNov 9, 2022Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.43
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.43
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7ngp
  • Surface level: 0.43
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_12316.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.6531 Å
Density
Contour LevelBy AUTHOR: 0.31 / Movie #1: 0.43
Minimum - Maximum-0.3081485 - 1.1991671
Average (Standard dev.)0.00803976 (±0.075750455)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 423.1936 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.65310156251.65310156251.6531015625
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z423.194423.194423.194
α/β/γ90.00090.00090.000
start NX/NY/NZ278280246
NX/NY/NZ474891
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.3081.1990.008

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Supplemental data

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Sample components

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Entire : D1-state of LonP1 hexameric complex

EntireName: D1-state of LonP1 hexameric complex
Components
  • Complex: D1-state of LonP1 hexameric complex
    • Protein or peptide: Lon protease homolog, mitochondrial
  • Ligand: ADENOSINE-5'-DIPHOSPHATE

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Supramolecule #1: D1-state of LonP1 hexameric complex

SupramoleculeName: D1-state of LonP1 hexameric complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
Molecular weightExperimental: 600 KDa

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Macromolecule #1: Lon protease homolog, mitochondrial

MacromoleculeName: Lon protease homolog, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 6 / Enantiomer: LEVO / EC number: endopeptidase La
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 93.201383 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: HLPLIAITRN PVFPRFIKII EVKNKKLVEL LRRKVRLAQP YVGVFLKRDD SNESDVVESL DEIYHTGTFA QIHEMQDLGD KLRMIVMGH RRVHISRQLE VEPEEPEAEN KHKPRRKSKR GKKEAEDELS ARHPAELAME PTPELPAEVL MVEVENVVHE D FQVTEEVK ...String:
HLPLIAITRN PVFPRFIKII EVKNKKLVEL LRRKVRLAQP YVGVFLKRDD SNESDVVESL DEIYHTGTFA QIHEMQDLGD KLRMIVMGH RRVHISRQLE VEPEEPEAEN KHKPRRKSKR GKKEAEDELS ARHPAELAME PTPELPAEVL MVEVENVVHE D FQVTEEVK ALTAEIVKTI RDIIALNPLY RESVLQMMQA GQRVVDNPIY LSDMGAALTG AESHELQDVL EETNIPKRLY KA LSLLKKE FELSKLQQRL GREVEEKIKQ THRKYLLQEQ LKIIKKELGL EKDDKDAIEE KFRERLKELV VPKHVMDVVD EEL SKLGLL DNHSSEFNVT RNYLDWLTSI PWGKYSNENL DLARAQAVLE EDHYGMEDVK KRILEFIAVS QLRGSTQGKI LCFY GPPGV GKTSIARSIA RALNREYFRF SVGGMTDVAE IKGHRRTYVG AMPGKIIQCL KKTKTENPLI LIDEVDKIGR GYQGD PSSA LLELLDPEQN ANFLDHYLDV PVDLSKVLFI CTANVTDTIP EPLRDRMEMI NVSGYVAQEK LAIAERYLVP QARALC GLD ESKAKLSSDV LTLLIKQYCR ESGVRNLQKQ VEKVLRKSAY KIVSGEAESV EVTPENLQDF VGKPVFTVER MYDVTPP GV VMGLAWTAMG GSTLFVETSL RRPQDKDAKG DKDGSLEVTG QLGEVMKESA RIAYTFARAF LMQHAPANDY LVTSHIHL H VPEGATPKDG PSAGCTIVTA LLSLAMGRPV RQNLAMTGEV SLTGKILPVG GIKEKTIAAK RAGVTCIVLP AENKKDFYD LAAFITEGLE VHFVEHYREI FDIAFP

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Macromolecule #2: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 2 / Number of copies: 6 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM / Adenosine diphosphate

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.45 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 64.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Details: ab-initio; The coordinates of 7ngl subunits, including bound nucleotides, were fitted as rigid bodies into the low resolution density of the LonP1 D1-state. The N-domains (res. 123-410) were ...Details: ab-initio; The coordinates of 7ngl subunits, including bound nucleotides, were fitted as rigid bodies into the low resolution density of the LonP1 D1-state. The N-domains (res. 123-410) were fitted separately from the combined A- and protease domains (res 411-1001). The connecting loops (res 405-415) were reconnected with good geometry. Clashes between the rigid bodies were not corrected due to the low resolution.
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 15.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software: (Name: RELION, cryoSPARC) / Number images used: 15000

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Atomic model buiding 1

RefinementProtocol: RIGID BODY FIT
Output model

PDB-7ngp:
D1-state of wild type human mitochondrial LONP1 protease

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