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- EMDB-70448: Cryo-EM structure of OS9-SEL1L-HRD1 dimer -

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Basic information

Entry
Database: EMDB / ID: EMD-70448
TitleCryo-EM structure of OS9-SEL1L-HRD1 dimer
Map data
Sample
  • Complex: OS9-SEL1L-HRD1 Dimer
    • Protein or peptide: E3 ubiquitin-protein ligase synoviolin
    • Protein or peptide: Protein sel-1 homolog 1
    • Protein or peptide: Isoform 2 of Protein OS-9
KeywordsERAD / SEL1L / OS9 / HRD1 / MEMBRANE PROTEIN
Function / homology
Function and homology information


glycosylation-dependent protein binding / negative regulation of retrograde protein transport, ER to cytosol / protein retention in ER lumen / Hrd1p ubiquitin ligase complex / endoplasmic reticulum mannose trimming / Hedgehog ligand biogenesis / Hrd1p ubiquitin ligase ERAD-L complex / endoplasmic reticulum quality control compartment / ABC-family proteins mediated transport / XBP1(S) activates chaperone genes ...glycosylation-dependent protein binding / negative regulation of retrograde protein transport, ER to cytosol / protein retention in ER lumen / Hrd1p ubiquitin ligase complex / endoplasmic reticulum mannose trimming / Hedgehog ligand biogenesis / Hrd1p ubiquitin ligase ERAD-L complex / endoplasmic reticulum quality control compartment / ABC-family proteins mediated transport / XBP1(S) activates chaperone genes / immature B cell differentiation / Derlin-1 retrotranslocation complex / triglyceride metabolic process / retrograde protein transport, ER to cytosol / ubiquitin-specific protease binding / protein secretion / protein targeting / smooth endoplasmic reticulum / protein K48-linked ubiquitination / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / endoplasmic reticulum unfolded protein response / ERAD pathway / Notch signaling pathway / ER Quality Control Compartment (ERQC) / endomembrane system / response to endoplasmic reticulum stress / Hh mutants are degraded by ERAD / Hedgehog ligand biogenesis / Defective CFTR causes cystic fibrosis / RING-type E3 ubiquitin transferase / ABC-family proteins mediated transport / ubiquitin protein ligase activity / unfolded protein binding / protein-folding chaperone binding / ATPase binding / carbohydrate binding / protease binding / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / protein stabilization / protein ubiquitination / endoplasmic reticulum lumen / endoplasmic reticulum membrane / endoplasmic reticulum / zinc ion binding / nucleoplasm / membrane
Similarity search - Function
Protein OS9-like domain / Protein OS-9-like / Glucosidase II beta subunit-like protein / : / : / Sel1 repeat / Sel1-like repeat / Sel1-like repeats. / Mannose-6-phosphate receptor binding domain superfamily / MRH domain ...Protein OS9-like domain / Protein OS-9-like / Glucosidase II beta subunit-like protein / : / : / Sel1 repeat / Sel1-like repeat / Sel1-like repeats. / Mannose-6-phosphate receptor binding domain superfamily / MRH domain / MRH domain profile. / Ring finger domain / Fibronectin type II domain / Fibronectin type II domain superfamily / Fibronectin type II domain / Fibronectin type-II collagen-binding domain signature. / Fibronectin type-II collagen-binding domain profile. / Fibronectin type 2 domain / Kringle-like fold / Ring finger / Zinc finger RING-type profile. / Zinc finger, RING-type / Tetratricopeptide-like helical domain superfamily / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
Protein OS-9 / E3 ubiquitin-protein ligase synoviolin / Protein sel-1 homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.64 Å
AuthorsLin L / Maldosevic E / Jomaa A / Qi L
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R35GM130292 United States
CitationJournal: bioRxiv / Year: 2025
Title: Structural basis and pathological implications of the dimeric OS9-SEL1L-HRD1 ERAD Core Complex.
Authors: Liangguang Leo Lin / Emir Maldosevic / Linyao Elina Zhou / Ahmad Jomaa / Ling Qi
Abstract: The SEL1L-HRD1 complex represents the most conserved branch of endoplasmic reticulum (ER)-associated degradation (ERAD), a critical pathway that clears misfolded proteins to maintain ER proteostasis. ...The SEL1L-HRD1 complex represents the most conserved branch of endoplasmic reticulum (ER)-associated degradation (ERAD), a critical pathway that clears misfolded proteins to maintain ER proteostasis. However, the molecular organization and pathogenic mechanisms of mammalian ERAD have remained elusive. Here, we report the first cryo-EM structure of the core mammalian ERAD complex, comprising the ER lectin OS9, SEL1L, and the E3 ubiquitin ligase HRD1. The structure, validated by mutagenesis and crosslinking assays, reveals a dimeric assembly of the core complex in which SEL1L and OS9 form a claw-like configuration in the ER lumen that mediates substrate engagement, while HRD1 dimerizes within the membrane to facilitate substrate translocation. Pathogenic SEL1L mutations at the SEL1L-OS9 (Gly585Asp) and SEL1L-HRD1 (Ser658Pro) interfaces disrupt complex formation and impair ERAD activity. A newly identified disease-associated HRD1 variant (Ala91Asp), located in transmembrane helix 3, impairs HRD1 dimerization and substrate processing, underscoring the functional necessity of this interface and HRD1 dimerization. Finally, the structure also reveals two methionine-rich crevices flanking the HRD1 dimer, suggestive of substrate-conducting channels analogous to those in the ER membrane protein complex (EMC). These findings establish a structural framework for mammalian ERAD and elucidate how mutations destabilizing this machinery contribute to human disease.
SUMMARY: The dimeric structure of the human SEL1L-HRD1 ERAD core complex reveals key architectural and functional principles underlying the recognition and processing of misfolded proteins linked to human disease.
History
DepositionApr 30, 2025-
Header (metadata) releaseJul 30, 2025-
Map releaseJul 30, 2025-
UpdateJul 30, 2025-
Current statusJul 30, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70448.png

Downloads & links

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Map

FileDownload / File: emd_70448.map.gz / Format: CCP4 / Size: 443.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 488 pix.
= 318.176 Å		0.65 Å/pix.
x 488 pix.
= 318.176 Å		0.65 Å/pix.
x 488 pix.
= 318.176 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.652 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.038
Minimum - Maximum-0.4677961 - 0.6036077
Average (Standard dev.)-0.00024972996 (±0.008883532)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions488488488
Spacing488488488
CellA=B=C: 318.176 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_70448_msk_1.map
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Half map: #1

Fileemd_70448_half_map_1.map
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Half map: #2

Fileemd_70448_half_map_2.map
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Sample components

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Entire : OS9-SEL1L-HRD1 Dimer

EntireName: OS9-SEL1L-HRD1 Dimer
Components
  • Complex: OS9-SEL1L-HRD1 Dimer
    • Protein or peptide: E3 ubiquitin-protein ligase synoviolin
    • Protein or peptide: Protein sel-1 homolog 1
    • Protein or peptide: Isoform 2 of Protein OS-9

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Supramolecule #1: OS9-SEL1L-HRD1 Dimer

SupramoleculeName: OS9-SEL1L-HRD1 Dimer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: E3 ubiquitin-protein ligase synoviolin

MacromoleculeName: E3 ubiquitin-protein ligase synoviolin / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: RING-type E3 ubiquitin transferase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 67.744586 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MFRTAVMMAA SLALTGAVVA HAYYLKHQFY PTVVYLTKSS PSMAVLYIQA FVLVFLLGKV MGKVFFGQLR AAEMEHLLER SWYAVTETC LAFTVFRDDF SPRFVALFTL LLFLKCFHWL AEDRVDFMER SPNISWLFHC RIVSLMFLLG ILDFLFVSHA Y HSILTRGA ...String:
MFRTAVMMAA SLALTGAVVA HAYYLKHQFY PTVVYLTKSS PSMAVLYIQA FVLVFLLGKV MGKVFFGQLR AAEMEHLLER SWYAVTETC LAFTVFRDDF SPRFVALFTL LLFLKCFHWL AEDRVDFMER SPNISWLFHC RIVSLMFLLG ILDFLFVSHA Y HSILTRGA SVQLVFGFEY AILMTMVLTI FIKYVLHSVD LQSENPWDNK AVYMLYTELF TGFIKVLLYM AFMTIMIKVH TF PLFAIRP MYLAMRQFKK AVTDAIMSRR AIRNMNTLYP DATPEELQAM DNVCIICREE MVTGAKRLPC NHIFHTSCLR SWF QRQQTC PTCRMDVLRA SLPAQSPPPP EPADQGPPPA PHPPPLLPQP PNFPQGLLPP FPPGMFPLWP PMGPFPPVPP PPSS GEAVA PPSTSAAALS RPSGAATTTA AGTSATAASA TASGPGSGSA PEAGPAPGFP FPPPWMGMPL PPPFAFPPMP VPPAG FAGL TPEELRALEG HERQHLEARL QSLRNIHTLL DAAMLQINQY LTVLASLGPP RPATSVNSTE ETATTVVAAA SSTSIP SSE ATTPTPGASP PAPEMERPPA PESVGTEEMP EDGEPDAAEL RRRRLQKLES PVAH

UniProtKB: E3 ubiquitin-protein ligase synoviolin

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Macromolecule #2: Protein sel-1 homolog 1

MacromoleculeName: Protein sel-1 homolog 1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 88.435148 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MQVRVRLSLL LLCAVLLGSA AATSDDKTNQ DDSLDSKSSL PTDESVKDHT TTGKVVAGQI FVDSEEAEVE SLLQDEEDSS KTQEEEISF LESPNPSSKT YEELKRVRKP VLTAIEGTAH GEPCHFPFLF LDKEYDECTS DGREDGRLWC ATTYDYKTDE K WGFCETEE ...String:
MQVRVRLSLL LLCAVLLGSA AATSDDKTNQ DDSLDSKSSL PTDESVKDHT TTGKVVAGQI FVDSEEAEVE SLLQDEEDSS KTQEEEISF LESPNPSSKT YEELKRVRKP VLTAIEGTAH GEPCHFPFLF LDKEYDECTS DGREDGRLWC ATTYDYKTDE K WGFCETEE DAAKRRQMQE AEMIYQAGMK ILNGSNRKSQ KREAYRYLQK AAGMNHTKAL ERVSYALLFG DYLTQNIQAA KE MFEKLTE EGSPKGQTGL GFLYASGLGV NSSQAKALVY YTFGALGGNL IAHMILGYRY WAGIGVLQSC ESALTHYRLV ANH VASDIS LTGGSVVQRI RLPDEVENPG MNSGMLEEDL IQYYQFLAEK GDVQAQVGLG QLHLHGGRGV EQNHQRAFDY FNLA ANAGN SHAMAFLGKM YSEGSDIVPQ SNETALHYFK KAADMGNPVG QSGLGMAYLY GRGVQVNYDL ALKYFQKAAE QGWVD GQLQ LGSMYYNGIG VKRDYKQALK YFNLASQGGH ILAFYNLAQM HASGTGVMRS CHTAVELFKN VCERGRWSER LMTAYN SYK DEDYNAAVVQ YLLLAEQGYE VAQSNAAFIL DQREATIVGE NETYPRALLH WNRAASQGYT VARIKLGDYH FYGFGTD VD YETAFIHYRL ASEQQHSAQA MFNLGYMHEK GLGIKQDIHL AKRFYDMAAE ASPDAQVPVF LALCKLGVVY FLQYIREA N IRDLFTQLDM DQLLGPEWDL YLMTIIALLL GTVIAYRQRQ HQDIPVPRPP GPRPAPPQQE GPPEQQPPQ

UniProtKB: Protein sel-1 homolog 1

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Macromolecule #3: Isoform 2 of Protein OS-9

MacromoleculeName: Isoform 2 of Protein OS-9 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 69.335352 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAAETLLSSL LGLLLLGLLL PASLTGGVGS LNLEELSEMR YGIEILPLPV MGGQSQSSDV VIVSSKYKQR YECRLPAGAI HFQREREEE TPAYQGPGIP ELLSPMRDAP CLLKTKDWWT YEFCYGRHIQ QYHMEDSEIK GEVLYLGYYQ SAFDWDDETA K ASKQHRLK ...String:
MAAETLLSSL LGLLLLGLLL PASLTGGVGS LNLEELSEMR YGIEILPLPV MGGQSQSSDV VIVSSKYKQR YECRLPAGAI HFQREREEE TPAYQGPGIP ELLSPMRDAP CLLKTKDWWT YEFCYGRHIQ QYHMEDSEIK GEVLYLGYYQ SAFDWDDETA K ASKQHRLK RYHSQTYGNG SKCDLNGRPR EAEVRFLCDE GAGISGDYID RVDEPLSCSY VLTIRTPRLC PHPLLRPPPS AA PQAILCH PSLQPEEYMA YVQRQADSKQ YGDKIIEELQ DLGPQVWSET KSGVAPQKMA GASPTKDDSK DSDFWKMLNE PED QAPGGE EVPAEEQDPS PEAADSASGA PNDFQNNVQV KVIRSPADLI RFIEELKGGT KKGKPNIGQE QPVDDAAEVP QREP EKERG DPERQREMEE EEDEDEDEDE DEDERQLLGE FEKELEGILL PSDRDRLRSE VKAGMERELE NIIQETEKEL DPDGL KKES ERDRAMLALT STLNKLIKRL EEKQSPELVK KHKKKRVVPK KPPPSPQPTG KIEIKIVRPW AEGTEEGARW LTDEDT RNL KEIFFNILVP GAEEAQKERQ RQKELESNYR RVWGSPGGEG TGDLDEFDF

UniProtKB: Protein OS-9

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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

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.64 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 192786
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-9og0:
Cryo-EM structure of OS9-SEL1L-HRD1 dimer

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