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- PDB-9llk: The cryo-EM structure of the heterododecameric human Derlin-1/p97... -

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Basic information

Entry
Database: PDB / ID: 9llk
TitleThe cryo-EM structure of the heterododecameric human Derlin-1/p97 complex
Components
  • Derlin-1
  • Transitional endoplasmic reticulum ATPase
KeywordsMEMBRANE PROTEIN / ERAD
Function / homology
Function and homology information


Derlin-1-VIMP complex / signal recognition particle binding / endoplasmic reticulum quality control compartment / flavin adenine dinucleotide catabolic process / VCP-NSFL1C complex / endoplasmic reticulum stress-induced pre-emptive quality control / endosome to lysosome transport via multivesicular body sorting pathway / BAT3 complex binding / cellular response to arsenite ion / cytoplasmic ubiquitin ligase complex ...Derlin-1-VIMP complex / signal recognition particle binding / endoplasmic reticulum quality control compartment / flavin adenine dinucleotide catabolic process / VCP-NSFL1C complex / endoplasmic reticulum stress-induced pre-emptive quality control / endosome to lysosome transport via multivesicular body sorting pathway / BAT3 complex binding / cellular response to arsenite ion / cytoplasmic ubiquitin ligase complex / Derlin-1 retrotranslocation complex / positive regulation of protein K63-linked deubiquitination / ATPase complex / protein-DNA covalent cross-linking repair / deubiquitinase activator activity / positive regulation of oxidative phosphorylation / cytoplasm protein quality control / regulation of protein localization to chromatin / ubiquitin-modified protein reader activity / cellular response to misfolded protein / mitotic spindle disassembly / VCP-NPL4-UFD1 AAA ATPase complex / positive regulation of mitochondrial membrane potential / vesicle-fusing ATPase / K48-linked polyubiquitin modification-dependent protein binding / regulation of aerobic respiration / NAD+ metabolic process / retrograde protein transport, ER to cytosol / stress granule disassembly / ubiquitin-specific protease binding / regulation of synapse organization / positive regulation of ATP biosynthetic process / ubiquitin-like protein ligase binding / RHOH GTPase cycle / intracellular membrane-bounded organelle / MHC class I protein binding / response to unfolded protein / autophagosome maturation / negative regulation of hippo signaling / HSF1 activation / endoplasmic reticulum to Golgi vesicle-mediated transport / polyubiquitin modification-dependent protein binding / mitophagy / interstrand cross-link repair / ATP metabolic process / protein unfolding / proteasome complex / ribosome-associated ubiquitin-dependent protein catabolic process / Attachment and Entry / endoplasmic reticulum unfolded protein response / Protein methylation / ERAD pathway / negative regulation of smoothened signaling pathway / viral genome replication / positive regulation of protein ubiquitination / translesion synthesis / negative regulation of protein localization to chromatin / rescue of stalled cytosolic ribosome / macroautophagy / lipid droplet / Josephin domain DUBs / establishment of protein localization / proteasomal protein catabolic process / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / positive regulation of protein-containing complex assembly / protein destabilization / Hh mutants are degraded by ERAD / positive regulation of non-canonical NF-kappaB signal transduction / ADP binding / Dengue Virus Genome Translation and Replication / Translesion Synthesis by POLH / Hedgehog ligand biogenesis / Defective CFTR causes cystic fibrosis / AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274) / ABC-family protein mediated transport / autophagy / cytoplasmic stress granule / Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide / positive regulation of protein catabolic process / Aggrephagy / positive regulation of canonical Wnt signaling pathway / double-strand break repair / azurophil granule lumen / Ovarian tumor domain proteases / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / late endosome / KEAP1-NFE2L2 pathway / site of double-strand break / cellular response to heat / E3 ubiquitin ligases ubiquitinate target proteins / ATPase binding / Neddylation / signaling receptor activity / protease binding / secretory granule lumen / protein phosphatase binding / ubiquitin-dependent protein catabolic process / ficolin-1-rich granule lumen / proteasome-mediated ubiquitin-dependent protein catabolic process / early endosome
Similarity search - Function
Derlin / Der1-like family / Rhomboid-like superfamily / AAA ATPase, CDC48 family / Cell division protein 48 (CDC48), N-terminal domain / : / CDC48, N-terminal subdomain / Cell division protein 48 (CDC48) N-terminal domain / CDC48, domain 2 / Cell division protein 48 (CDC48), domain 2 ...Derlin / Der1-like family / Rhomboid-like superfamily / AAA ATPase, CDC48 family / Cell division protein 48 (CDC48), N-terminal domain / : / CDC48, N-terminal subdomain / Cell division protein 48 (CDC48) N-terminal domain / CDC48, domain 2 / Cell division protein 48 (CDC48), domain 2 / Cell division protein 48 (CDC48) domain 2 / CDC48 domain 2-like superfamily / Aspartate decarboxylase-like domain superfamily / AAA ATPase, AAA+ lid domain / AAA+ lid domain / ATPase, AAA-type, conserved site / AAA-protein family signature. / ATPase family associated with various cellular activities (AAA) / ATPase, AAA-type, core / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / Transitional endoplasmic reticulum ATPase / Derlin-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.55 Å
AuthorsCao, Y. / Wang, Q. / Yao, D. / Rao, B. / Xia, Y. / Li, W. / Li, S. / Shen, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82072468(YC) China
CitationJournal: Commun Biol / Year: 2025
Title: Cryo-EM structure of the human Derlin-1/p97 complex reveals a hexameric channel in ERAD.
Authors: Qian Wang / Deqiang Yao / Bing Rao / Ying Xia / Wenguo Li / Shaobai Li / Mi Cao / Yafeng Shen / An Qin / Yu Cao /
Abstract: The ER-associated degradation (ERAD) pathway retrotranslocates misfolded proteins from the ER lumen to the cytoplasm for proteasomal degradation. Derlin-1 and p97 are central to this process, forming ...The ER-associated degradation (ERAD) pathway retrotranslocates misfolded proteins from the ER lumen to the cytoplasm for proteasomal degradation. Derlin-1 and p97 are central to this process, forming a canonical 4:6 complex with tetrameric Derlin-1. Using cryo-electron microscopy, we identify a novel human Derlin-1/p97 complex with a 6:6 stoichiometry, where hexameric Derlin-1 assembles as three dimers. This hexameric channel forms a significantly larger trans-ER membrane tunnel, potentially accommodating bulkier substrates. Structural comparisons revealed conformational flexibility in Derlin-1, suggesting the "U"-shaped tetramer may act as an intermediate in hexamer formation. The formation of this hexameric channel is mediated by interactions with p97 and appears dependent on p97's ATPase activity, which provides the driving force for the transition between the tetrameric channel conformation to the intermediate "U"-shaped conformation. These findings highlight the dynamic nature of the Derlin-1/p97 complex and its implications for understanding ERAD retrotranslocation.
History
DepositionJan 17, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 29, 2025Provider: repository / Type: Initial release
Revision 1.0Oct 29, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Oct 29, 2025Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Oct 29, 2025Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 29, 2025Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Oct 29, 2025Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Oct 29, 2025Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Transitional endoplasmic reticulum ATPase
C: Transitional endoplasmic reticulum ATPase
V: Derlin-1
W: Derlin-1
F: Transitional endoplasmic reticulum ATPase
A: Transitional endoplasmic reticulum ATPase
Z: Derlin-1
U: Derlin-1
D: Transitional endoplasmic reticulum ATPase
E: Transitional endoplasmic reticulum ATPase
X: Derlin-1
Y: Derlin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)689,27524
Polymers684,14912
Non-polymers5,12612
Water00
1


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

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Components

#1: Protein
Transitional endoplasmic reticulum ATPase / TER ATPase / 15S Mg(2+)-ATPase p97 subunit / Valosin-containing protein / VCP


Mass: 87546.711 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: VCP, HEL-220, HEL-S-70 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P55072, vesicle-fusing ATPase
#2: Protein
Derlin-1 / Degradation in endoplasmic reticulum protein 1 / DERtrin-1 / Der1-like protein 1


Mass: 26478.100 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DERL1, DER1, UNQ243/PRO276 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BUN8
#3: Chemical
ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: ADP, energy-carrying molecule*YM
Has ligand of interestY
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: The cryogenic electron-microscopic structure of the heterododecameric human Derlin-1/p97 complex
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.73 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenConc.: 15 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281.15 K

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 81000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1500 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 2.9 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 15 eV

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C3 (3 fold cyclic)
3D reconstructionResolution: 3.55 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 129127 / Algorithm: FOURIER SPACE / Symmetry type: POINT

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