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- EMDB-68281: CryoEM structure of Human LonP1-TFAM complex -

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Basic information

Entry
Database: EMDB / ID: EMD-68281
TitleCryoEM structure of Human LonP1-TFAM complex
Map dataCryoEM map of Human LonP1-TFAM complex
Sample
  • Complex: Human LonP1 protease with TFAM
    • Protein or peptide: Lon protease homolog, mitochondrial
    • Protein or peptide: TFAM substrate
  • Ligand: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: MAGNESIUM ION
KeywordsHuman Lon protease / Complex / STRUCTURAL PROTEIN
Function / homology
Function and homology information


oxidation-dependent protein catabolic process / response to aluminum ion / PH domain binding / endopeptidase La / mitochondrial protein catabolic process / G-quadruplex DNA binding / ATP-dependent peptidase activity / protein quality control for misfolded or incompletely synthesized proteins / mitochondrial nucleoid / insulin receptor substrate binding ...oxidation-dependent protein catabolic process / response to aluminum ion / PH domain binding / endopeptidase La / mitochondrial protein catabolic process / G-quadruplex DNA binding / ATP-dependent peptidase activity / protein quality control for misfolded or incompletely synthesized proteins / mitochondrial nucleoid / insulin receptor substrate binding / Mitochondrial unfolded protein response (UPRmt) / chaperone-mediated protein complex assembly / DNA polymerase binding / response to hormone / negative regulation of insulin receptor signaling pathway / Mitochondrial protein degradation / : / mitochondrion organization / ADP binding / single-stranded DNA binding / cellular response to oxidative stress / sequence-specific DNA binding / response to hypoxia / single-stranded RNA binding / 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 / 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: 3.22 Å
AuthorsLi M / Liu H / Zhang K / Li S
Funding support China, 1 items
OrganizationGrant numberCountry
Other government China
CitationJournal: Life (Basel) / Year: 2026
Title: Structural Analysis of Human LonP1 Protease Bound with the Native Substrate.
Authors: Ming Li / Hongwei Liu / Shengchun Zhang / Qijun Gao / Shanshan Li / Junfeng Wang / Kaiming Zhang /
Abstract: The human mitochondrial Lon protease (LonP1) is a central regulator of mitochondrial DNA copy number and metabolic reprogramming. However, the structural basis for how LonP1 recognizes native ...The human mitochondrial Lon protease (LonP1) is a central regulator of mitochondrial DNA copy number and metabolic reprogramming. However, the structural basis for how LonP1 recognizes native physiological substrates remains elusive. Here, we present the high-resolution cryo-EM structure of the human LonP1 hexamer actively engaging its native substrate, TFAM. The reconstruction reveals a distinct bipartite search-and-shred mechanism. Unlike its bacterial homologs, the human N-terminal domain (NTD) adopts a compact architecture acting as a selective vestibule to recruit and initially unfold the substrate tertiary structure. Subsequently, the polypeptide is threaded through the central channel via a hand-over-hand mechanism driven by a spiral array of aromatic pore-loops. This structural framework provides a mechanistic rationale for the spatial segregation of LonP1 and offers a template for targeting mitochondrial proteostasis in human diseases.
History
DepositionJan 12, 2026-
Header (metadata) releaseApr 22, 2026-
Map releaseApr 22, 2026-
UpdateApr 22, 2026-
Current statusApr 22, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_68281.png

Downloads & links

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Map

FileDownload / File: emd_68281.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM map of Human LonP1-TFAM complex
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 384 pix.
= 314.88 Å		0.82 Å/pix.
x 384 pix.
= 314.88 Å		0.82 Å/pix.
x 384 pix.
= 314.88 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.42588282 - 0.632968
Average (Standard dev.)0.00038814876 (±0.01701947)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 314.88 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: CryoEM half map of Human LonP1-TFAM complex

Fileemd_68281_half_map_1.map
AnnotationCryoEM half map of Human LonP1-TFAM complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: CryoEM half map of Human LonP1-TFAM complex

Fileemd_68281_half_map_2.map
AnnotationCryoEM half map of Human LonP1-TFAM complex
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human LonP1 protease with TFAM

EntireName: Human LonP1 protease with TFAM
Components
  • Complex: Human LonP1 protease with TFAM
    • Protein or peptide: Lon protease homolog, mitochondrial
    • Protein or peptide: TFAM substrate
  • Ligand: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
  • Ligand: MAGNESIUM ION

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Supramolecule #1: Human LonP1 protease with TFAM

SupramoleculeName: Human LonP1 protease with TFAM / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)

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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: 65.514312 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: LLKKEFELSK LQQRLGREVE EKIKQTHRKY LLQEQLKIIK KELGLEKDDK DAIEEKFRER LKELVVPKHV MDVVDEELSK LGLLDNHSS EFNVTRNYLD WLTSIPWGKY SNENLDLARA QAVLEEDHYG MEDVKKRILE FIAVSQLRGS TQGKILCFYG P PGVGKTSI ...String:
LLKKEFELSK LQQRLGREVE EKIKQTHRKY LLQEQLKIIK KELGLEKDDK DAIEEKFRER LKELVVPKHV MDVVDEELSK LGLLDNHSS EFNVTRNYLD WLTSIPWGKY SNENLDLARA QAVLEEDHYG MEDVKKRILE FIAVSQLRGS TQGKILCFYG P PGVGKTSI ARSIARALNR EYFRFSVGGM TDVAEIKGHR RTYVGAMPGK IIQCLKKTKT ENPLILIDEV DKIGRGYQGD PS SALLELL DPEQNANFLD HYLDVPVDLS KVLFICTANV TDTIPEPLRD RMEMINVSGY VAQEKLAIAE RYLVPQARAL CGL DESKAK LSSDVLTLLI KQYCRESGVR NLQKQVEKVL RKSAYKIVSG EAESVEVTPE NLQDFVGKPV FTVERMYDVT PPGV VMGLA WTAMGGSTLF VETSLRRPQD KDAKGDKDGS LEVTGQLGEV MKESARIAYT FARAFLMQHA PANDYLVTSH IHLHV PEGA TPKDGPSAGC TIVTALLSLA MGRPVRQNLA MTGEVSLTGK ILPVGGIKEK TIAAKRAGVT CIVLPAENKK DFYDLA AFI TEGLEVHFVE HYREIFDIAF PD

UniProtKB: Lon protease homolog, mitochondrial

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Macromolecule #2: TFAM substrate

MacromoleculeName: TFAM substrate / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 2.400951 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)

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Macromolecule #3: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER

MacromoleculeName: PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / type: ligand / ID: 3 / Number of copies: 3 / Formula: AGS
Molecular weightTheoretical: 523.247 Da
Chemical component information

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

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Macromolecule #4: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 4 / Number of copies: 2 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

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

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Macromolecule #5: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 5 / Number of copies: 2 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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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

Concentration0.3 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 429368
CTF correctionType: NONE
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.22 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.7) / Number images used: 99919
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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