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- PDB-9rjc: Apo Structure of the Human Signal Peptidase -

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Basic information

Entry
Database: PDB / ID: 9rjc
TitleApo Structure of the Human Signal Peptidase
Components
  • Signal peptidase complex catalytic subunit SEC11A
  • Signal peptidase complex subunit 1
  • Signal peptidase complex subunit 2
  • Signal peptidase complex subunit 3
KeywordsMEMBRANE PROTEIN / Signal Peptidase Complex / protein biogenesis / secretory pathway / membrane thinning
Function / homology
Function and homology information


signal peptidase complex / Maturation of DENV proteins / signal peptidase I / signal peptidase activity / : / protein targeting to ER / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / virion assembly / Regulation of CDH1 posttranslational processing and trafficking to plasma membrane / Maturation of hRSV A proteins ...signal peptidase complex / Maturation of DENV proteins / signal peptidase I / signal peptidase activity / : / protein targeting to ER / Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) / virion assembly / Regulation of CDH1 posttranslational processing and trafficking to plasma membrane / Maturation of hRSV A proteins / Synthesis, secretion, and deacylation of Ghrelin / SRP-dependent cotranslational protein targeting to membrane / response to virus / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / peptidase activity / viral protein processing / serine-type endopeptidase activity / endoplasmic reticulum membrane / endoplasmic reticulum / proteolysis
Similarity search - Function
Peptidase S26B / Signal peptidase complex subunit 3 / Signal peptidase complex subunit 2 / Signal peptidase subunit / Microsomal signal peptidase 25 kDa subunit (SPC25) / Signal peptidase complex subunit 1 / Microsomal signal peptidase 12 kDa subunit (SPC12) / Peptidase S26A, signal peptidase I, conserved site / Signal peptidases I signature 3. / Peptidase S26A, signal peptidase I, serine active site ...Peptidase S26B / Signal peptidase complex subunit 3 / Signal peptidase complex subunit 2 / Signal peptidase subunit / Microsomal signal peptidase 25 kDa subunit (SPC25) / Signal peptidase complex subunit 1 / Microsomal signal peptidase 12 kDa subunit (SPC12) / Peptidase S26A, signal peptidase I, conserved site / Signal peptidases I signature 3. / Peptidase S26A, signal peptidase I, serine active site / Signal peptidases I serine active site. / Peptidase S26 / Peptidase S24/S26A/S26B/S26C / Peptidase S24-like / LexA/Signal peptidase-like superfamily
Similarity search - Domain/homology
Signal peptidase complex subunit 3 / Signal peptidase complex catalytic subunit SEC11A / Signal peptidase complex subunit 2 / Signal peptidase complex subunit 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsLiaci, A.M. / Vismpas, D. / Skalidis, I. / Koh, F.A. / Abhay, K. / Forster, G.F.
Funding support Netherlands, 2items
OrganizationGrant numberCountry
Netherlands Organisation for Scientific Research (NWO)OCENW.M.22.151 Netherlands
Netherlands Organisation for Scientific Research (NWO)184.034.014 Netherlands
CitationJournal: Nat Commun / Year: 2026
Title: Structural basis of signal peptide recognition by the signal peptidase complex.
Authors: A Manuel Liaci / Dimitrios Vismpas / Lisbeth R Kjølbye / Ioannis Skalidis / Gilberto P Pereira / Adrian Fujiet Koh / Mariska Gröllers-Mulderij / Abhay Kotecha / Paulo C T Souza / Friedrich Förster /
Abstract: The signal peptidase complex (SPC) is responsible for cleaving signal peptides (SPs) from approximately 10% of the human proteome. SPs are characterized by a tripartite structure, consisting of an N- ...The signal peptidase complex (SPC) is responsible for cleaving signal peptides (SPs) from approximately 10% of the human proteome. SPs are characterized by a tripartite structure, consisting of an N-terminal n-region, a central helical h-region and a C-terminal c-region, each defined by rather general chemical properties rather than strict sequence conservation. Despite their sequence diversity, SPC recognizes and processes SPs with exquisite specificity. Here, we present a 2.6 Å cryo-EM map of the human SPC-A, one of two SPC paralogs, bound to a model SP. The c-region binds to a hydrophobic binding groove near the active site, a narrow gate marks the transition from c- to h-region, and the h-region localizes in a transmembrane (TM) window. Substrate engagement stabilizes N- and C-terminal helices of Sec11A, which frame the SP and are unresolved in the apo structure. Molecular dynamics (MD) simulations confirm a stable hydrogen-bonding network at the c-region and indicate dynamic interactions within a thinned lipid environment at the TM window. AlphaFold modeling supports this binding mode across physiological SPs. Collectively, our structural and computational analyses explain how the SPC achieves its specificity by combining the selectivity of the luminal binding groove and of the transmembrane window.
History
DepositionJun 12, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 27, 2026Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
Revision 1.0May 27, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Jun 3, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Jun 3, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Signal peptidase complex catalytic subunit SEC11A
B: Signal peptidase complex subunit 1
C: Signal peptidase complex subunit 2
D: Signal peptidase complex subunit 3


Theoretical massNumber of molelcules
Total (without water)67,7324
Polymers67,7324
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Signal peptidase complex catalytic subunit SEC11A / Endopeptidase SP18 / Microsomal signal peptidase 18 kDa subunit / SPase 18 kDa subunit / SEC11 ...Endopeptidase SP18 / Microsomal signal peptidase 18 kDa subunit / SPase 18 kDa subunit / SEC11 homolog A / SEC11-like protein 1 / SPC18


Mass: 20394.979 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SEC11A, SEC11L1, SPC18, SPCS4A / Production host: Homo sapiens (human) / References: UniProt: P67812, signal peptidase I
#2: Protein Signal peptidase complex subunit 1 / Microsomal signal peptidase 12 kDa subunit / SPase 12 kDa subunit


Mass: 7386.763 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SPCS1, SPC12, HSPC033 / Production host: Homo sapiens (human) / References: UniProt: Q9Y6A9
#3: Protein Signal peptidase complex subunit 2 / Microsomal signal peptidase 25 kDa subunit / SPase 25 kDa subunit


Mass: 20338.516 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SPCS2, KIAA0102, SPC25 / Production host: Homo sapiens (human) / References: UniProt: Q15005
#4: Protein Signal peptidase complex subunit 3 / Microsomal signal peptidase 22/23 kDa subunit / SPC22/23 / SPase 22/23 kDa subunit


Mass: 19611.531 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SPCS3, SPC22, UNQ1841/PRO3567 / Production host: Homo sapiens (human) / References: UniProt: P61009
Has protein modificationN

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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: Apo Structure of the Human Signal Peptidase Complex / Type: COMPLEX / Entity ID: #3, #1, #4, #2 / Source: RECOMBINANT
Molecular weightValue: 0.09334 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Cell: HEK 293
Buffer solutionpH: 7.8
Details: addition of 1.5 mM fluorinated, fos-choline (FFosC, Anatrace) directly before vitrification
Buffer component
IDConc.NameFormulaBuffer-ID
110 mMHEPES1
285 mMsodium chlorideNaCl1
30.0174 %DDM CHS1
41 mMEDTA1
SpecimenConc.: 4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil Active R2/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE-PROPANE / 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: 1200 nm / Nominal defocus min: 800 nm / Alignment procedure: COMA FREE
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 6537

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Processing

EM software
IDNameVersionCategoryDetails (eV)
1cryoSPARC3.3.1particle selection
2EPU3.1image acquisition
4cryoSPARC3.3.1CTF correction
7Coot0.9.8.3model fitting
9PHENIX1.20.1_4487model refinement
10cryoSPARC3.3.1initial Euler assignmentab initio
11cryoSPARC3.3.1final Euler assignmenthomogeneous refinement
12cryoSPARC3.3.1classificationnon uniform refinement
13cryoSPARC3.3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2457714
3D reconstructionResolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 516615 / Algorithm: SIMULTANEOUS ITERATIVE (SIRT) / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model buildingPDB-ID: 7P2P

7p2p


Accession code: 7P2P / Details: PDB / Source name: PDB / Type: experimental model

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