[English] 日本語
Yorodumi
- EMDB-22281: CryoEM structure of human presequence protease in partial closed ... -

+
Open data


ID or keywords:

Loading...

-
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 / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / collateral sprouting in absence of injury / growth cone filopodium / microglia development / hippocampal neuron apoptotic process / regulation of Wnt signaling pathway ...Mitochondrial protein import / Hydrolases; Acting on peptide bonds (peptidases); Metalloendopeptidases / amyloid-beta complex / growth cone lamellipodium / cellular response to norepinephrine stimulus / collateral sprouting in absence of injury / growth cone filopodium / microglia development / hippocampal neuron apoptotic process / regulation of Wnt signaling pathway / Formyl peptide receptors bind formyl peptides and many other ligands / axo-dendritic transport / axon midline choice point recognition / regulation of synapse structure or activity / positive regulation of synaptic transmission, cholinergic / astrocyte activation involved in immune response / NMDA selective glutamate receptor signaling pathway / regulation of spontaneous synaptic transmission / mating behavior / growth factor receptor binding / Insertion of tail-anchored proteins into the endoplasmic reticulum membrane / positive regulation of amyloid fibril formation / peptidase activator activity / PTB domain binding / Golgi-associated vesicle / Lysosome Vesicle Biogenesis / Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer's disease models / neuron remodeling / astrocyte projection / protein localization to mitochondrion / regulation of multicellular organism growth / nuclear envelope lumen / dendrite development / TRAF6 mediated NF-kB activation / positive regulation of protein metabolic process / negative regulation of long-term synaptic potentiation / signaling receptor activator activity / Notch signaling pathway / transition metal ion binding / Advanced glycosylation endproduct receptor signaling / The NLRP3 inflammasome / intracellular copper ion homeostasis / modulation of excitatory postsynaptic potential / main axon / ECM proteoglycans / positive regulation of T cell migration / response to insulin-like growth factor stimulus / regulation of presynapse assembly / extracellular matrix organization / swimming behavior / adult locomotory behavior / neuronal dense core vesicle / regulation of long-term neuronal synaptic plasticity / Purinergic signaling in leishmaniasis infection / positive regulation of calcium-mediated signaling / positive regulation of chemokine production / positive regulation of mitotic cell cycle / axonogenesis / cellular response to manganese ion / neuron projection maintenance / clathrin-coated pit / visual learning / cellular response to cAMP / astrocyte activation / synaptic cleft / Mitochondrial protein degradation / response to interleukin-1 / platelet alpha granule lumen / regulation of neuron apoptotic process / positive regulation of glycolytic process / learning / ionotropic glutamate receptor signaling pathway / locomotory behavior / cellular response to copper ion / endosome lumen / positive regulation of interleukin-1 beta production / central nervous system development / positive regulation of long-term synaptic potentiation / protein serine/threonine kinase binding / serine-type endopeptidase inhibitor activity / Post-translational protein phosphorylation / dendritic shaft / trans-Golgi network membrane / endocytosis / microglial cell activation / cellular response to nerve growth factor stimulus / regulation of translation / metalloendopeptidase activity / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of interleukin-6 production / positive regulation of JNK cascade / synapse organization / TAK1-dependent IKK and NF-kappa-B activation / Golgi lumen / recycling endosome / response to lead ion / cognition / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / cellular response to amyloid-beta / 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, heparin-binding / Amyloid A4 N-terminal heparin-binding / 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, E2 domain / E2 domain superfamily / Amyloidogenic glycoprotein, heparin-binding domain superfamily / 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

-
Structure visualization

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

emd_22281.png

Downloads & links

-
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
Brightness
Contrast
Others
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

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

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

-
Supplemental data

-
Mask #1

Fileemd_22281_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Additional map: #1

Fileemd_22281_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #1

Fileemd_22281_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Half map: #2

Fileemd_22281_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

-
Sample components

-
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

-
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)

-
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

-
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

-
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)

-
Experimental details

-
Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

-
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

-
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

+
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)

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more