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- EMDB-14119: Structure of the human MHC I peptide-loading complex editing module -

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Basic information

Entry
Database: EMDB / ID: EMD-14119
TitleStructure of the human MHC I peptide-loading complex editing module
Map data
Sample
  • Complex: editing module of peptide-loading complex
    • Protein or peptide: Beta-2-microglobulin
    • Protein or peptide: Tapasin
    • Protein or peptide: Protein disulfide-isomerase A3
    • Protein or peptide: HLA class I histocompatibility antigen, A-3 alpha chain
    • Protein or peptide: Calreticulin
Keywordsantigen processing / peptide proofreading / chaperones / MHC I / IMMUNE SYSTEM
Function / homology
Function and homology information


MHC class Ib protein complex assembly / peptide antigen stabilization / response to biphenyl / negative regulation of intracellular steroid hormone receptor signaling pathway / Calnexin/calreticulin cycle / MHC class I protein complex binding / cytolytic granule / nuclear receptor-mediated glucocorticoid signaling pathway / positive regulation of dendritic cell chemotaxis / Assembly of Viral Components at the Budding Site ...MHC class Ib protein complex assembly / peptide antigen stabilization / response to biphenyl / negative regulation of intracellular steroid hormone receptor signaling pathway / Calnexin/calreticulin cycle / MHC class I protein complex binding / cytolytic granule / nuclear receptor-mediated glucocorticoid signaling pathway / positive regulation of dendritic cell chemotaxis / Assembly of Viral Components at the Budding Site / ATF6 (ATF6-alpha) activates chaperone genes / protein disulfide-isomerase / cellular response to electrical stimulus / negative regulation of trophoblast cell migration / negative regulation of retinoic acid receptor signaling pathway / cortical granule / response to peptide / complement component C1q complex binding / endoplasmic reticulum quality control compartment / sarcoplasmic reticulum lumen / protein folding in endoplasmic reticulum / cellular response to lithium ion / disulfide oxidoreductase activity / nuclear export signal receptor activity / TAP2 binding / regulation of protein complex stability / TAP1 binding / cardiac muscle cell differentiation / C-type glycerophospholipase activity / response to glycoside / negative regulation of neuron differentiation / positive regulation of memory T cell activation / T cell mediated cytotoxicity directed against tumor cell target / positive regulation of CD8-positive, alpha-beta T cell activation / CD8-positive, alpha-beta T cell activation / positive regulation of CD8-positive, alpha-beta T cell proliferation / T cell mediated cytotoxicity / Scavenging by Class A Receptors / Scavenging by Class F Receptors / nuclear androgen receptor binding / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-dependent / response to testosterone / TAP complex binding / antigen processing and presentation of exogenous peptide antigen via MHC class I / Golgi medial cisterna / retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum / protein disulfide isomerase activity / lncRNA binding / CD8 receptor binding / smooth endoplasmic reticulum / protection from natural killer cell mediated cytotoxicity / hormone binding / protein-disulfide reductase activity / TAP binding / endoplasmic reticulum exit site / protein localization to nucleus / MHC class I protein binding / positive regulation of substrate adhesion-dependent cell spreading / detection of bacterium / antigen processing and presentation of endogenous peptide antigen via MHC class Ib / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent / molecular sequestering activity / protein export from nucleus / beta-2-microglobulin binding / T cell receptor binding / endocytic vesicle lumen / peptide binding / ERAD pathway / phagocytic vesicle / endoplasmic reticulum-Golgi intermediate compartment membrane / positive regulation of cell cycle / positive regulation of endothelial cell migration / protein folding chaperone / positive regulation of phagocytosis / acrosomal vesicle / response to endoplasmic reticulum stress / regulation of natural killer cell mediated immunity / early endosome lumen / positive regulation of T cell mediated cytotoxicity / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / lumenal side of endoplasmic reticulum membrane / regulation of iron ion transport / cellular response to virus / protein maturation / Maturation of DENV proteins / negative regulation of iron ion transport / negative regulation of forebrain neuron differentiation / antigen processing and presentation of exogenous peptide antigen via MHC class Ib / peptide antigen assembly with MHC class I protein complex / ER to Golgi transport vesicle membrane / HFE-transferrin receptor complex / positive regulation of type II interferon production / MHC class I peptide loading complex / transferrin transport / negative regulation of receptor-mediated endocytosis / cellular response to iron ion / positive regulation of T cell cytokine production
Similarity search - Function
Protein disulfide-isomerase A3, first redox inactive TRX-like domain b / Tapasin / Calreticulin / Calreticulin family repeated motif signature. / Calreticulin/calnexin / Calreticulin/calnexin, P domain superfamily / Calreticulin/calnexin, conserved site / Calreticulin family / Calreticulin family signature 1. / Calreticulin family signature 2. ...Protein disulfide-isomerase A3, first redox inactive TRX-like domain b / Tapasin / Calreticulin / Calreticulin family repeated motif signature. / Calreticulin/calnexin / Calreticulin/calnexin, P domain superfamily / Calreticulin/calnexin, conserved site / Calreticulin family / Calreticulin family signature 1. / Calreticulin family signature 2. / Protein disulphide isomerase / Thioredoxin-like domain / Disulphide isomerase / Endoplasmic reticulum targeting sequence. / Thioredoxin / Thioredoxin family active site. / Thioredoxin, conserved site / : / Thioredoxin domain profile. / Thioredoxin domain / MHC class I, alpha chain, C-terminal / MHC_I C-terminus / MHC class I alpha chain, alpha1 alpha2 domains / Class I Histocompatibility antigen, domains alpha 1 and 2 / Beta-2-Microglobulin / : / MHC class I-like antigen recognition-like / MHC class I-like antigen recognition-like superfamily / MHC classes I/II-like antigen recognition protein / : / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Concanavalin A-like lectin/glucanase domain superfamily / Thioredoxin-like superfamily / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Tapasin / HLA class I histocompatibility antigen, A alpha chain / Calreticulin / Protein disulfide-isomerase A3 / Beta-2-microglobulin
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.73 Å
AuthorsDomnick A / Susac L
Funding supportEuropean Union, 2 items
OrganizationGrant numberCountry
German Research Foundation (DFG)TA157/12-1European Union
European Research Council (ERC)789121European Union
CitationJournal: Nat Commun / Year: 2022
Title: Molecular basis of MHC I quality control in the peptide loading complex.
Authors: Alexander Domnick / Christian Winter / Lukas Sušac / Leon Hennecke / Mario Hensen / Nicole Zitzmann / Simon Trowitzsch / Christoph Thomas / Robert Tampé /
Abstract: Major histocompatibility complex class I (MHC I) molecules are central to adaptive immunity. Their assembly, epitope selection, and antigen presentation are controlled by the MHC I glycan through a ...Major histocompatibility complex class I (MHC I) molecules are central to adaptive immunity. Their assembly, epitope selection, and antigen presentation are controlled by the MHC I glycan through a sophisticated network of chaperones and modifying enzymes. However, the mechanistic integration of the corresponding processes remains poorly understood. Here, we determine the multi-chaperone-client interaction network of the peptide loading complex (PLC) and report the PLC editing module structure by cryogenic electron microscopy at 3.7 Å resolution. Combined with epitope-proofreading studies of the PLC in near-native lipid environment, these data show that peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan, which only becomes accessible for processing by α-glucosidase II upon loading of optimal epitopes. Our work reveals allosteric coupling between peptide-MHC I assembly and glycan processing. This inter-process communication defines the onset of an adaptive immune response and provides a prototypical example of the tightly coordinated events in endoplasmic reticulum quality control.
History
DepositionJan 3, 2022-
Header (metadata) releaseJul 20, 2022-
Map releaseJul 20, 2022-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_14119.png

Downloads & links

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Map

FileDownload / File: emd_14119.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 360 pix.
= 378. Å		1.05 Å/pix.
x 360 pix.
= 378. Å		1.05 Å/pix.
x 360 pix.
= 378. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.05 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.16
Minimum - Maximum-0.6351286 - 1.8569355
Average (Standard dev.)0.0015905458 (±0.018048683)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 377.99997 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : editing module of peptide-loading complex

EntireName: editing module of peptide-loading complex
Components
  • Complex: editing module of peptide-loading complex
    • Protein or peptide: Beta-2-microglobulin
    • Protein or peptide: Tapasin
    • Protein or peptide: Protein disulfide-isomerase A3
    • Protein or peptide: HLA class I histocompatibility antigen, A-3 alpha chain
    • Protein or peptide: Calreticulin

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Supramolecule #1: editing module of peptide-loading complex

SupramoleculeName: editing module of peptide-loading complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Beta-2-microglobulin

MacromoleculeName: Beta-2-microglobulin / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.74816 KDa
SequenceString:
IQRTPKIQVY SRHPAENGKS NFLNCYVSGF HPSDIEVDLL KNGERIEKVE HSDLSFSKDW SFYLLYYTEF TPTEKDEYAC RVNHVTLSQ PKIVKWDRDM

UniProtKB: Beta-2-microglobulin

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Macromolecule #2: Tapasin

MacromoleculeName: Tapasin / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.761184 KDa
SequenceString: GPAVIECWFV EDASGKGLAK RPGALLLRQG PGEPPPRPDL DPELYLSVHD PAGALQAAFR RYPRGAPAPH CEMSRFVPLP ASAKWASGL TPAQNCPRAL DGAWLMVSIS SPVLSLSSLL RPQPEPQQEP VLITMATVVL TVLTHTPAPR VRLGQDALLD L SFAYMPPT ...String:
GPAVIECWFV EDASGKGLAK RPGALLLRQG PGEPPPRPDL DPELYLSVHD PAGALQAAFR RYPRGAPAPH CEMSRFVPLP ASAKWASGL TPAQNCPRAL DGAWLMVSIS SPVLSLSSLL RPQPEPQQEP VLITMATVVL TVLTHTPAPR VRLGQDALLD L SFAYMPPT SEAASSLAPG PPPFGLEWRR QHLGKGHLLL AATPGLNGQM PAAQEGAVAF AAWDDDEPWG PWTGNGTFWL PR VQPFQEG TYLATIHLPY LQGQVTLELA VYKPPKVSLM PATLARAAPG EAPPELLCLV SHFYPSGGLE VEWELRGGPG GRS QKAEGQ RWLSALRHHS DGSVSLSGHL QPPPVTTEQH GARYACRIHH PSLPASGRSA EVTLEVAGLS GPSLEDSVGL FLSA FLLLG LFKALGWAAV YLSTCKDSKK KAE

UniProtKB: Tapasin

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Macromolecule #3: Protein disulfide-isomerase A3

MacromoleculeName: Protein disulfide-isomerase A3 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: protein disulfide-isomerase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 54.341102 KDa
SequenceString: SDVLELTDDN FESRISDTGS AGLMLVEFFA PWCGHCKRLA PEYEAAATRL KGIVPLAKVD CTANTNTCNK YGVSGYPTLK IFRDGEEAG AYDGPRTADG IVSHLKKQAG PASVPLRTEE EFKKFISDKD ASIVGFFDDS FSEAHSEFLK AASNLRDNYR F AHTNVESL ...String:
SDVLELTDDN FESRISDTGS AGLMLVEFFA PWCGHCKRLA PEYEAAATRL KGIVPLAKVD CTANTNTCNK YGVSGYPTLK IFRDGEEAG AYDGPRTADG IVSHLKKQAG PASVPLRTEE EFKKFISDKD ASIVGFFDDS FSEAHSEFLK AASNLRDNYR F AHTNVESL VNEYDDNGEG IILFRPSHLT NKFEDKTVAY TEQKMTSGKI KKFIQENIFG ICPHMTEDNK DLIQGKDLLI AY YDVDYEK NAKGSNYWRN RVMMVAKKFL DAGHKLNFAV ASRKTFSHEL SDFGLESTAG EIPVVAIRTA KGEKFVMQEE FSR DGKALE RFLQDYFDGN LKRYLKSEPI PESNDGPVKV VVAENFDEIV NNENKDVLIE FYAPWCGHCK NLEPKYKELG EKLS KDPNI VIAKMDATAN DVPSPYEVRG FPTIYFSPAN KKLNPKKYEG GRELSDFISY LQREATNPPV IQEEKPKKKK KAQED L

UniProtKB: Protein disulfide-isomerase A3

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Macromolecule #4: HLA class I histocompatibility antigen, A-3 alpha chain

MacromoleculeName: HLA class I histocompatibility antigen, A-3 alpha chain
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.363535 KDa
SequenceString: GSHSMRYFFT SVSRPGRGEP RFIAVGYVDD TQFVRFDSDA ASQRMEPRAP WIEQEGPEYW DQETRNVKAQ SQTDRVDLGT LRGYYNQSE AGSHTIQIMY GCDVGSDGRF LRGYRQDAYD GKDYIALNED LRSWTAADMA AQITKRKWEA AHEAEQLRAY L DGTCVEWL ...String:
GSHSMRYFFT SVSRPGRGEP RFIAVGYVDD TQFVRFDSDA ASQRMEPRAP WIEQEGPEYW DQETRNVKAQ SQTDRVDLGT LRGYYNQSE AGSHTIQIMY GCDVGSDGRF LRGYRQDAYD GKDYIALNED LRSWTAADMA AQITKRKWEA AHEAEQLRAY L DGTCVEWL RRYLENGKET LQRTDPPKTH MTHHPISDHE ATLRCWALGF YPAEITLTWQ RDGEDQTQDT ELVETRPAGD GT FQKWAAV VVPSGEEQRY TCHVQHEGLP KPLTLRWELS SQPTIPIVGI IAGLVLLGAV ITGAVVAAVM WRRKSSDRKG GSY TQAASS DSAQGSDVSL TACKV

UniProtKB: HLA class I histocompatibility antigen, A alpha chain

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Macromolecule #5: Calreticulin

MacromoleculeName: Calreticulin / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.523211 KDa
SequenceString: EPAVYFKEQF LDGDGWTSRW IESKHKSDFG KFVLSSGKFY GDEEKDKGLQ TSQDARFYAL SASFEPFSNK GQTLVVQFTV KHEQNIDCG GGYVKLFPNS LDQTDMHGDS EYNIMFGPDI CGPGTKKVHV IFNYKGKNVL INKDIRCKDD EFTHLYTLIV R PDNTYEVK ...String:
EPAVYFKEQF LDGDGWTSRW IESKHKSDFG KFVLSSGKFY GDEEKDKGLQ TSQDARFYAL SASFEPFSNK GQTLVVQFTV KHEQNIDCG GGYVKLFPNS LDQTDMHGDS EYNIMFGPDI CGPGTKKVHV IFNYKGKNVL INKDIRCKDD EFTHLYTLIV R PDNTYEVK IDNSQVESGS LEDDWDFLPP KKIKDPDASK PEDWDERAKI DDPTDSKPED WDKPEHIPDP DAKKPEDWDE EM DGEWEPP VIQNPEYKGE WKPRQIDNPD YKGTWIHPEI DNPEYSPDPS IYAYDNFGVL GLDLWQVKSG TIFDNFLITN DEA YAEEFG NETWGVTKAA EKQMKDKQDE EQRLKEEEED KKRKEEEEAE DKEDDEDKDE DEEDEEDKEE DEEEDVPGQA KDEL

UniProtKB: Calreticulin

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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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 68.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.73 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 97952
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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