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- EMDB-16923: Human Mitochondrial Lon Y394F Mutant ADP Bound -

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Basic information

Entry
Database: EMDB / ID: EMD-16923
TitleHuman Mitochondrial Lon Y394F Mutant ADP Bound
Map data
Sample
  • Complex: Human mitochondrial Lon protease
    • Protein or peptide: Lon protease homolog, mitochondrial
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
KeywordsHuman mitochondrial AAA+ protease / motor protein / HYDROLASE
Function / homology
Function and homology information


oxidation-dependent protein catabolic process / PH domain binding / mitochondrial protein catabolic process / endopeptidase La / G-quadruplex DNA binding / 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 / mitochondrial protein catabolic process / endopeptidase La / G-quadruplex DNA binding / 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 / negative regulation of insulin receptor signaling pathway / DNA polymerase binding / Mitochondrial protein degradation / proteolysis involved in protein catabolic process / mitochondrion organization / protein catabolic process / ADP binding / 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 / identical protein binding / membrane / cytosol
Similarity search - Function
Lon protease homologue, chloroplastic/mitochondrial / : / Lon protease, bacterial/eukaryotic-type / Lon protease AAA+ ATPase lid domain / 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 homologue, chloroplastic/mitochondrial / : / Lon protease, bacterial/eukaryotic-type / Lon protease AAA+ ATPase lid domain / 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 N-terminal domain profile. / Lon protease, N-terminal domain / Lon protease, N-terminal domain superfamily / 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: 3.89 Å
AuthorsKereiche S / Bauer JA / Matyas P / Novacek J / Kutejova E
Funding support Slovakia, European Union, Czech Republic, 7 items
OrganizationGrant numberCountry
Other governmentAPVV-15-0375 Slovakia
Other governmentAPVV-19-0298 Slovakia
Other governmentVEGA-2/0069/23 Slovakia
Other governmentVEGA-2/0131/20 Slovakia
European Regional Development FundITMS:305011X666European Union
Ministry of Education, Youth and Sports of the Czech RepublicCIISB project LM2018127 Czech Republic
Czech Science Foundation1825144Y Czech Republic
CitationJournal: Sci Rep / Year: 2024
Title: Polyphosphate and tyrosine phosphorylation in the N-terminal domain of the human mitochondrial Lon protease disrupts its functions.
Authors: Nina Kunová / Gabriela Ondrovičová / Jacob A Bauer / Veronika Krajčovičová / Matyáš Pinkas / Barbora Stojkovičová / Henrieta Havalová / Veronika Lukáčová / Lenka Kohútová / ...Authors: Nina Kunová / Gabriela Ondrovičová / Jacob A Bauer / Veronika Krajčovičová / Matyáš Pinkas / Barbora Stojkovičová / Henrieta Havalová / Veronika Lukáčová / Lenka Kohútová / Július Košťan / Lucia Martináková / Peter Baráth / Jiří Nováček / Sebastian Zoll / Sami Kereϊche / Eva Kutejová / Vladimír Pevala /
Abstract: Phosphorylation plays a crucial role in the regulation of many fundamental cellular processes. Phosphorylation levels are increased in many cancer cells where they may promote changes in ...Phosphorylation plays a crucial role in the regulation of many fundamental cellular processes. Phosphorylation levels are increased in many cancer cells where they may promote changes in mitochondrial homeostasis. Proteomic studies on various types of cancer identified 17 phosphorylation sites within the human ATP-dependent protease Lon, which degrades misfolded, unassembled and oxidatively damaged proteins in mitochondria. Most of these sites were found in Lon's N-terminal (NTD) and ATPase domains, though little is known about the effects on their function. By combining the biochemical and cryo-electron microscopy studies, we show the effect of Tyr186 and Tyr394 phosphorylations in Lon's NTD, which greatly reduce all Lon activities without affecting its ability to bind substrates or perturbing its tertiary structure. A substantial reduction in Lon's activities is also observed in the presence of polyphosphate, whose amount significantly increases in cancer cells. Our study thus provides an insight into the possible fine-tuning of Lon activities in human diseases, which highlights Lon's importance in maintaining proteostasis in mitochondria.
History
DepositionMar 28, 2023-
Header (metadata) releaseApr 10, 2024-
Map releaseApr 10, 2024-
UpdateMay 15, 2024-
Current statusMay 15, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_16923.png

Downloads & links

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Map

FileDownload / File: emd_16923.map.gz / Format: CCP4 / Size: 282.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

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AxesZ (Sec.)Y (Row.)X (Col.)
0.78 Å/pix.
x 420 pix.
= 328.86 Å		0.78 Å/pix.
x 420 pix.
= 328.86 Å		0.78 Å/pix.
x 420 pix.
= 328.86 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.783 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.077
Minimum - Maximum-0.12115579 - 0.3052016
Average (Standard dev.)0.0010217767 (±0.013706187)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions420420420
Spacing420420420
CellA=B=C: 328.86 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_16923_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_16923_half_map_2.map
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Sample components

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Entire : Human mitochondrial Lon protease

EntireName: Human mitochondrial Lon protease
Components
  • Complex: Human mitochondrial Lon protease
    • Protein or peptide: Lon protease homolog, mitochondrial
  • Ligand: ADENOSINE-5'-DIPHOSPHATE

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Supramolecule #1: Human mitochondrial Lon protease

SupramoleculeName: Human mitochondrial Lon protease / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human) / Organelle: mitochondria

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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: 98.183852 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGHHHHHHDY DIPTTENLYF QGAHMTIPDV FPHLPLIAIT RNPVFPRFIK IIEVKNKKLV ELLRRKVRLA QPYVGVFLKR DDSNESDVV ESLDEIYHTG TFAQIHEMQD LGDKLRMIVM GHRRVHISRQ LEVEPEEPEA ENKHKPRRKS KRGKKEAEDE L SARHPAEL ...String:
MGHHHHHHDY DIPTTENLYF QGAHMTIPDV FPHLPLIAIT RNPVFPRFIK IIEVKNKKLV ELLRRKVRLA QPYVGVFLKR DDSNESDVV ESLDEIYHTG TFAQIHEMQD LGDKLRMIVM GHRRVHISRQ LEVEPEEPEA ENKHKPRRKS KRGKKEAEDE L SARHPAEL AMEPTPELPA EVLMVEVENV VHEDFQVTEE VKALTAEIVK TIRDIIALNP LYRESVLQMM QAGQRVVDNP IY LSDMGAA LTGAESHELQ DVLEETNIPK RLYKALSLLK KEFELSKLQQ RLGREVEEKI KQTHRKFLLQ EQLKIIKKEL GLE KDDKDA IEEKFRERLK ELVVPKHVMD VVDEELSKLG LLDNHSSEFN VTRNYLDWLT SIPWGKYSNE NLDLARAQAV LEED HYGME DVKKRILEFI AVSQLRGSTQ GKILCFYGPP GVGKTSIARS IARALNREYF RFSVGGMTDV AEIKGHRRTY VGAMP GKII QCLKKTKTEN PLILIDEVDK IGRGYQGDPS SALLELLDPE QNANFLDHYL DVPVDLSKVL FICTANVTDT IPEPLR DRM EMINVSGYVA QEKLAIAERY LVPQARALCG LDESKAKLSS DVLTLLIKQY CRESGVRNLQ KQVEKVLRKS AYKIVSG EA ESVEVTPENL QDFVGKPVFT VERMYDVTPP GVVMGLAWTA MGGSTLFVET SLRRPQDKDA KGDKDGSLEV TGQLGEVM K ESARIAYTFA RAFLMQHAPA NDYLVTSHIH LHVPEGATPK DGPSAGCTIV TALLSLAMGR PVRQNLAMTG EVSLTGKIL PVGGIKEKTI AAKRAGVTCI VLPAENKKDF YDLAAFITEG LEVHFVEHYR EIFDIAFPDE QAEALAVER

UniProtKB: Lon protease homolog, mitochondrial

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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

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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

BufferpH: 7
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 2.0 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.89 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 34462
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelPDB ID:

7nfy


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8oka:
Human Mitochondrial Lon Y394F Mutant ADP Bound

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