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- PDB-8uwc: Site-one protease without SPRING -

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Basic information

Entry
Database: PDB / ID: 8uwc
TitleSite-one protease without SPRING
ComponentsMembrane-bound transcription factor site-1 protease
KeywordsSIGNALING PROTEIN / serine protease cholesterol metabolism zymogen activation Protein complex glycoprotein secretory pathway
Function / homology
Function and homology information


site-1 protease / CREB3 factors activate genes / ATF6-mediated unfolded protein response / ATF6 (ATF6-alpha) activates chaperones / ATF6B (ATF6-beta) activates chaperones / regulation of cholesterol biosynthetic process / Assembly of active LPL and LIPC lipase complexes / membrane protein intracellular domain proteolysis / regulation of vesicle-mediated transport / Regulation of cholesterol biosynthesis by SREBP (SREBF) ...site-1 protease / CREB3 factors activate genes / ATF6-mediated unfolded protein response / ATF6 (ATF6-alpha) activates chaperones / ATF6B (ATF6-beta) activates chaperones / regulation of cholesterol biosynthetic process / Assembly of active LPL and LIPC lipase complexes / membrane protein intracellular domain proteolysis / regulation of vesicle-mediated transport / Regulation of cholesterol biosynthesis by SREBP (SREBF) / Golgi stack / lysosome organization / mitotic G2 DNA damage checkpoint signaling / cholesterol metabolic process / endoplasmic reticulum unfolded protein response / response to endoplasmic reticulum stress / protein maturation / Post-translational protein phosphorylation / protein processing / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / protein import into nucleus / endoplasmic reticulum lumen / Golgi membrane / serine-type endopeptidase activity / endoplasmic reticulum membrane / Golgi apparatus / proteolysis
Similarity search - Function
Site-1 peptidase catalytic domain / : / : / : / Membrane-bound Site-1 Protease Family N-terminal domain / MBTPS1, fourth GATase-like domain / MBTPS1, third Ig-like domain / Peptidase S8, subtilisin, His-active site / : / Serine proteases, subtilase family, histidine active site. ...Site-1 peptidase catalytic domain / : / : / : / Membrane-bound Site-1 Protease Family N-terminal domain / MBTPS1, fourth GATase-like domain / MBTPS1, third Ig-like domain / Peptidase S8, subtilisin, His-active site / : / Serine proteases, subtilase family, histidine active site. / Serine proteases, subtilase family, serine active site. / Peptidase S8, subtilisin, Ser-active site / Peptidase S8, subtilisin-related / Serine proteases, subtilase domain profile. / Peptidase S8/S53 domain superfamily / Subtilase family / Peptidase S8/S53 domain
Similarity search - Domain/homology
Membrane-bound transcription factor site-1 protease
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.27 Å
AuthorsKober, D.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R00GM141261 United States
CitationJournal: Nat Commun / Year: 2024
Title: SPRING licenses S1P-mediated cleavage of SREBP2 by displacing an inhibitory pro-domain.
Authors: Sebastian Hendrix / Vincent Dartigue / Hailee Hall / Shrankhla Bawaria / Jenina Kingma / Bilkish Bajaj / Noam Zelcer / Daniel L Kober /
Abstract: Site-one protease (S1P) conducts the first of two cleavage events in the Golgi to activate Sterol regulatory element binding proteins (SREBPs) and upregulate lipogenic transcription. S1P is also ...Site-one protease (S1P) conducts the first of two cleavage events in the Golgi to activate Sterol regulatory element binding proteins (SREBPs) and upregulate lipogenic transcription. S1P is also required for a wide array of additional signaling pathways. A zymogen serine protease, S1P matures through autoproteolysis of two pro-domains, with one cleavage event in the endoplasmic reticulum (ER) and the other in the Golgi. We recently identified the SREBP regulating gene, (SPRING), which enhances S1P maturation and is necessary for SREBP signaling. Here, we report the cryo-EM structures of S1P and S1P-SPRING at sub-2.5 Å resolution. SPRING activates S1P by dislodging its inhibitory pro-domain and stabilizing intra-domain contacts. Functionally, SPRING licenses S1P to cleave its cognate substrate, SREBP2. Our findings reveal an activation mechanism for S1P and provide insights into how spatial control of S1P activity underpins cholesterol homeostasis.
History
DepositionNov 6, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 10, 2024Provider: repository / Type: Initial release
Revision 1.1Jul 24, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.2Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Membrane-bound transcription factor site-1 protease
hetero molecules


Theoretical massNumber of molelcules
Total (without water)114,1052
Polymers113,8841
Non-polymers2211
Water1,74797
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable, gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Membrane-bound transcription factor site-1 protease / Endopeptidase S1P / Subtilisin/kexin-isozyme 1 / SKI-1


Mass: 113883.789 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MBTPS1, KIAA0091, S1P, SKI1 / Production host: Homo sapiens (human) / References: UniProt: Q14703, site-1 protease
#2: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 97 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Matured site-1 protease / Type: COMPLEX
Details: FLAG-S1P-His purified using NiNTA chromatography and gel filtration.
Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.12 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5 / Details: 50 mM HEPES-NaOH and 150 mM NaCl
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaCl1
250 mMHEPES buffered with sodium hydroxideHEPES-NaOH1
SpecimenConc.: 0.6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 600 nm
Image recordingAverage exposure time: 3.5 sec. / Electron dose: 55 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 6139
EM imaging opticsEnergyfilter name: TFS Selectris / Energyfilter slit width: 5 eV

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Processing

EM software
IDNameVersionCategory
2SerialEMimage acquisition
10cryoSPARC4.2initial Euler assignment
11cryoSPARC4.2final Euler assignment
12cryoSPARC4.2classification
13cryoSPARC4.23D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.27 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 659523 / Symmetry type: POINT

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