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- EMDB-22281: CryoEM structure of human presequence protease in partial closed ... -

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Basic information

Entry
Database: EMDB / ID: EMD-22281
TitleCryoEM structure of human presequence protease in partial closed state 1
Map data
Sample
  • Complex: CryoEM map of Human Presequence Protease in partial close state 1
    • Protein or peptide: Presequence protease, mitochondrial
    • Protein or peptide: Amyloid-beta precursor protein
    • Protein or peptide: Amyloid-beta precursor protein
KeywordsPartial open state / HYDROLASE
Function / homology
Function and homology information


Mitochondrial protein import / amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / growth cone filopodium / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / microglia development / collateral sprouting in absence of injury / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport ...Mitochondrial protein import / amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / growth cone filopodium / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / microglia development / collateral sprouting in absence of injury / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / regulation of Wnt signaling pathway / hippocampal neuron apoptotic process / axon midline choice point recognition / astrocyte activation involved in immune response / regulation of synapse structure or activity / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / growth factor receptor binding / peptidase activator activity / : / Golgi-associated vesicle / PTB domain binding / positive regulation of amyloid fibril formation / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / astrocyte projection / Lysosome Vesicle Biogenesis / neuron remodeling / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / nuclear envelope lumen / dendrite development / positive regulation of protein metabolic process / TRAF6 mediated NF-kB activation / negative regulation of long-term synaptic potentiation / signaling receptor activator activity / Advanced glycosylation endproduct receptor signaling / transition metal ion binding / main axon / The NLRP3 inflammasome / modulation of excitatory postsynaptic potential / regulation of multicellular organism growth / intracellular copper ion homeostasis / ECM proteoglycans / regulation of presynapse assembly / positive regulation of T cell migration / neuronal dense core vesicle / response to insulin-like growth factor stimulus / Purinergic signaling in leishmaniasis infection / positive regulation of chemokine production / Notch signaling pathway / cellular response to manganese ion / swimming behavior / clathrin-coated pit / extracellular matrix organization / neuron projection maintenance / astrocyte activation / positive regulation of calcium-mediated signaling / positive regulation of mitotic cell cycle / ionotropic glutamate receptor signaling pathway / Mitochondrial protein degradation / response to interleukin-1 / axonogenesis / protein serine/threonine kinase binding / platelet alpha granule lumen / regulation of neuron apoptotic process / cellular response to copper ion / cellular response to cAMP / positive regulation of glycolytic process / central nervous system development / dendritic shaft / trans-Golgi network membrane / endosome lumen / positive regulation of long-term synaptic potentiation / positive regulation of interleukin-1 beta production / adult locomotory behavior / learning / Post-translational protein phosphorylation / locomotory behavior / serine-type endopeptidase inhibitor activity / microglial cell activation / enzyme activator activity / positive regulation of non-canonical NF-kappaB signal transduction / cellular response to nerve growth factor stimulus / TAK1-dependent IKK and NF-kappa-B activation / protein processing / recycling endosome / metalloendopeptidase activity / synapse organization / regulation of long-term neuronal synaptic plasticity / visual learning / positive regulation of JNK cascade / response to lead ion / Golgi lumen / positive regulation of interleukin-6 production / cognition / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to amyloid-beta / endocytosis / metallopeptidase activity / neuron projection development
Similarity search - Function
: / Peptidase M16C associated / Peptidase M16C associated / PreP C-terminal domain / Peptidase M16C associated / Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. ...: / Peptidase M16C associated / Peptidase M16C associated / PreP C-terminal domain / Peptidase M16C associated / Amyloidogenic glycoprotein, copper-binding / Amyloidogenic glycoprotein, copper-binding domain conserved site / Amyloidogenic glycoprotein, copper-binding domain superfamily / Copper-binding of amyloid precursor, CuBD / Amyloid precursor protein (APP) copper-binding (CuBD) domain signature. / Amyloidogenic glycoprotein, amyloid-beta peptide superfamily / Beta-amyloid peptide (beta-APP) / Amyloidogenic glycoprotein, amyloid-beta peptide / Beta-amyloid precursor protein C-terminal / Amyloidogenic glycoprotein, intracellular domain, conserved site / Beta-amyloid precursor protein C-terminus / Amyloid precursor protein (APP) intracellular domain signature. / Amyloidogenic glycoprotein, extracellular / Amyloidogenic glycoprotein, heparin-binding / Amyloidogenic glycoprotein, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / Amyloid A4 N-terminal heparin-binding / E2 domain of amyloid precursor protein / Amyloid precursor protein (APP) E1 domain profile. / Amyloid precursor protein (APP) E2 domain profile. / amyloid A4 / Amyloidogenic glycoprotein / Peptidase M16, C-terminal / Peptidase M16 inactive domain / Peptidase M16, N-terminal / Insulinase (Peptidase family M16) / Metalloenzyme, LuxS/M16 peptidase-like / Proteinase inhibitor I2, Kunitz, conserved site / Pancreatic trypsin inhibitor (Kunitz) family signature. / BPTI/Kunitz family of serine protease inhibitors. / Pancreatic trypsin inhibitor Kunitz domain / Kunitz/Bovine pancreatic trypsin inhibitor domain / Pancreatic trypsin inhibitor (Kunitz) family profile. / Pancreatic trypsin inhibitor Kunitz domain superfamily / PH-like domain superfamily
Similarity search - Domain/homology
Amyloid-beta precursor protein / Presequence protease, mitochondrial
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsLiang WG / Zhao M
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)R01 GM121964 United States
CitationJournal: Nat Commun / Year: 2022
Title: Structural basis for the mechanisms of human presequence protease conformational switch and substrate recognition.
Authors: Wenguang G Liang / Juwina Wijaya / Hui Wei / Alex J Noble / Jordan M Mancl / Swansea Mo / David Lee / John V Lin King / Man Pan / Chang Liu / Carla M Koehler / Minglei Zhao / Clinton S ...Authors: Wenguang G Liang / Juwina Wijaya / Hui Wei / Alex J Noble / Jordan M Mancl / Swansea Mo / David Lee / John V Lin King / Man Pan / Chang Liu / Carla M Koehler / Minglei Zhao / Clinton S Potter / Bridget Carragher / Sheng Li / Wei-Jen Tang /
Abstract: Presequence protease (PreP), a 117 kDa mitochondrial M16C metalloprotease vital for mitochondrial proteostasis, degrades presequence peptides cleaved off from nuclear-encoded proteins and other ...Presequence protease (PreP), a 117 kDa mitochondrial M16C metalloprotease vital for mitochondrial proteostasis, degrades presequence peptides cleaved off from nuclear-encoded proteins and other aggregation-prone peptides, such as amyloid β (Aβ). PreP structures have only been determined in a closed conformation; thus, the mechanisms of substrate binding and selectivity remain elusive. Here, we leverage advanced vitrification techniques to overcome the preferential denaturation of one of two ~55 kDa homologous domains of PreP caused by air-water interface adsorption. Thereby, we elucidate cryoEM structures of three apo-PreP open states along with Aβ- and citrate synthase presequence-bound PreP at 3.3-4.6 Å resolution. Together with integrative biophysical and pharmacological approaches, these structures reveal the key stages of the PreP catalytic cycle and how the binding of substrates or PreP inhibitor drives a rigid body motion of the protein for substrate binding and catalysis. Together, our studies provide key mechanistic insights into M16C metalloproteases for future therapeutic innovations.
History
DepositionJul 7, 2020-
Header (metadata) releaseJul 7, 2021-
Map releaseJul 7, 2021-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.012
  • Imaged by UCSF Chimera
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  • Surface view colored by radius
  • Surface level: 0.012
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6xov
  • Surface level: 0.012
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22281.png

Downloads & links

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Map

FileDownload / File: emd_22281.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 256 pix.
= 218.88 Å		0.86 Å/pix.
x 256 pix.
= 218.88 Å		0.86 Å/pix.
x 256 pix.
= 218.88 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.855 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy EMDB: 0.01 / Movie #1: 0.012
Minimum - Maximum-0.019866075 - 0.050842203
Average (Standard dev.)0.0000023380235 (±0.0016944956)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 218.88 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8550.8550.855
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z218.880218.880218.880
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0200.0510.000

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Supplemental data

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Mask #1

Fileemd_22281_msk_1.map
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Additional map: #1

Fileemd_22281_additional_1.map
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Half map: #1

Fileemd_22281_half_map_1.map
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Half map: #2

Fileemd_22281_half_map_2.map
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Sample components

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Entire : CryoEM map of Human Presequence Protease in partial close state 1

EntireName: CryoEM map of Human Presequence Protease in partial close state 1
Components
  • Complex: CryoEM map of Human Presequence Protease in partial close state 1
    • Protein or peptide: Presequence protease, mitochondrial
    • Protein or peptide: Amyloid-beta precursor protein
    • Protein or peptide: Amyloid-beta precursor protein

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Supramolecule #1: CryoEM map of Human Presequence Protease in partial close state 1

SupramoleculeName: CryoEM map of Human Presequence Protease in partial close state 1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Presequence protease, mitochondrial

MacromoleculeName: Presequence protease, mitochondrial / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 114.901461 KDa
Recombinant expressionOrganism: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
SequenceString: MHHHHHHAAA CERALQYKLG DKIHGFTVNQ VTSVPELFLT AVKLTHDDTG ARYLHLARED TNNLFSVQFR TTPMDSTGVP HILEHTVLC GSQKYPCRDP FFKMLNRSLS TFMNAFTASD YTLYPFSTQN PKDFQNLLSV YLDATFFPCL RELDFWQEGW R LEHENPSD ...String:
MHHHHHHAAA CERALQYKLG DKIHGFTVNQ VTSVPELFLT AVKLTHDDTG ARYLHLARED TNNLFSVQFR TTPMDSTGVP HILEHTVLC GSQKYPCRDP FFKMLNRSLS TFMNAFTASD YTLYPFSTQN PKDFQNLLSV YLDATFFPCL RELDFWQEGW R LEHENPSD PQTPLVFKGV VFNEMKGAFT DNERIFSQHL QNRLLPDHTY SVVSGGDPLC IPELTWEQLK QFHATHYHPS NA RFFTYGN FPLEQHLKQI HEEALSKFQK IEPSTVVPAQ TPWDKPREFQ ITCGPDSFAT DPSKQTTVSV SFLLPDITDT FEA FTLSLL SSLLTSGPNS PFYKALIESG LGTDFSPDVG YNGYTREAYF SVGLQGIVEK DIETVRSLID RTIDEVVEKG FEDD RIEAL LHKIEIQMKH QSTSFGLMLT SYIASCWNHD GDPVELLKLG NQLAKFRQCL QENPKFLQEK VKQYFKNNQH KLTLS MRPD DKYHEKQAQV EATKLKQKVE ALSPGDRQQI YEKGLELRSQ QSKPQDASCL PALKVSDIEP TIPVTELDVV LTAGDI PVQ YCAQPTNGMV YFRAFSSLNT LPEELRPYVP LFCSVLTKLG CGLLDYREQA QQIELKTGGM SASPHVLPDD SHMDTYE QG VLFSSLCLDR NLPDMMQLWS EIFNNPCFEE EEHFKVLVKM TAQELANGIP DSGHLYASIR AGRTLTPAGD LQETFSGM D QVRLMKRIAE MTDIKPILRK LPRIKKHLLN GDNMRCSVNA TPQQMPQTEK AVEDFLRSIG RSKKERRPVR PHTVEKPVP SSSGGDAHVP HGSQVIRKLV MEPTFKPWQM KTHFLMPFPV NYVGECIRTV PYTDPDHASL KILARLMTAK FLHTEIREKG GAYGGGAKL SHNGIFTLYS YRDPNTIETL QSFGKAVDWA KSGKFTQQDI DEAKLSVFST VDAPVAPSDK GMDHFLYGLS D EMKQAHRE QLFAVSHDKL LAVSDRYLGT GKSTHGLAIL GPENPKIAKD PSWIIR

UniProtKB: Presequence protease, mitochondrial

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Macromolecule #2: Amyloid-beta precursor protein

MacromoleculeName: Amyloid-beta precursor protein / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 4.335852 KDa
SequenceString:
DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV

UniProtKB: Amyloid-beta precursor protein

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Macromolecule #3: Amyloid-beta precursor protein

MacromoleculeName: Amyloid-beta precursor protein / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 273.33 Da
SequenceString:
(UNK)(UNK)(UNK)

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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

Concentration2 mg/mL
BufferpH: 7.7
Details: 20 mM Tris, pH 7.7, 150 mM NaCl, 10mM KCl, 20 mM EDTA and 1 mM 2-mercaptoethanol
GridDetails: unspecified
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 308 K / Instrument: SPOTITON

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average exposure time: 6.0 sec. / Average electron dose: 66.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 70.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware - Name: CTFFIND / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 174537
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION
FSC plot (resolution estimation)

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