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- PDB-7qpd: Structure of the human MHC I peptide-loading complex editing module -

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Basic information

Entry
Database: PDB / ID: 7qpd
TitleStructure of the human MHC I peptide-loading complex editing module
Components
  • Beta-2-microglobulin
  • Calreticulin
  • HLA class I histocompatibility antigen, A-3 alpha chain
  • Protein disulfide-isomerase A3
  • Tapasin
KeywordsIMMUNE SYSTEM / antigen processing / peptide proofreading / chaperones / MHC I
Function / homology
Function and homology information


MHC class Ib protein complex assembly / peptide antigen stabilization / Tapasin-ERp57 complex / Calnexin/calreticulin cycle / MHC class I protein complex binding / TAP1 binding / TAP2 binding / cytolytic granule / positive regulation of dendritic cell chemotaxis / protein disulfide-isomerase ...MHC class Ib protein complex assembly / peptide antigen stabilization / Tapasin-ERp57 complex / Calnexin/calreticulin cycle / MHC class I protein complex binding / TAP1 binding / TAP2 binding / cytolytic granule / positive regulation of dendritic cell chemotaxis / protein disulfide-isomerase / cortical granule / Assembly of Viral Components at the Budding Site / negative regulation of trophoblast cell migration / ATF6 (ATF6-alpha) activates chaperone genes / negative regulation of retinoic acid receptor signaling pathway / cellular response to electrical stimulus / endoplasmic reticulum quality control compartment / nuclear receptor-mediated glucocorticoid signaling pathway / regulation of meiotic nuclear division / complement component C1q complex binding / sequestering of calcium ion / response to glycoside / sarcoplasmic reticulum lumen / disulfide oxidoreductase activity / protein folding in endoplasmic reticulum / nuclear export signal receptor activity / negative regulation of intracellular steroid hormone receptor signaling pathway / regulation of protein complex stability / hormone binding / cardiac muscle cell differentiation / molecular sequestering activity / phospholipase C activity / retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum / positive regulation of extrinsic apoptotic signaling pathway / cellular response to interleukin-7 / protein maturation by protein folding / Scavenging by Class F Receptors / Scavenging by Class A Receptors / cortical actin cytoskeleton organization / T cell mediated cytotoxicity directed against tumor cell target / positive regulation of memory T cell activation / TAP complex binding / nuclear androgen receptor binding / positive regulation of CD8-positive, alpha-beta T cell activation / CD8-positive, alpha-beta T cell activation / Golgi medial cisterna / positive regulation of CD8-positive, alpha-beta T cell proliferation / cellular response to lithium ion / CD8 receptor binding / response to testosterone / protein disulfide isomerase activity / MHC class I protein binding / antigen processing and presentation of exogenous peptide antigen via MHC class I / endoplasmic reticulum exit site / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-dependent / TAP binding / protein localization to nucleus / protection from natural killer cell mediated cytotoxicity / negative regulation of neuron differentiation / protein-disulfide reductase activity / smooth endoplasmic reticulum / beta-2-microglobulin binding / T cell receptor binding / positive regulation of cell cycle / detection of bacterium / ERAD pathway / extrinsic apoptotic signaling pathway / positive regulation of substrate adhesion-dependent cell spreading / protein folding chaperone / positive regulation of phagocytosis / endocytic vesicle lumen / protein export from nucleus / phagocytic vesicle / positive regulation of endothelial cell migration / endoplasmic reticulum-Golgi intermediate compartment membrane / response to endoplasmic reticulum stress / acrosomal vesicle / positive regulation of ferrous iron binding / positive regulation of transferrin receptor binding / positive regulation of receptor binding / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / negative regulation of receptor binding / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent / antigen processing and presentation of endogenous peptide antigen via MHC class Ib / lumenal side of endoplasmic reticulum membrane / cellular response to iron ion / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / peptide binding / cellular response to iron(III) ion / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / negative regulation of forebrain neuron differentiation / regulation of erythrocyte differentiation / ER to Golgi transport vesicle membrane / peptide antigen assembly with MHC class I protein complex / regulation of iron ion transport / response to molecule of bacterial origin / MHC class I peptide loading complex
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, conserved site / Thioredoxin family active 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 / Concanavalin A-like lectin/glucanase domain superfamily / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.73 Å
AuthorsDomnick, A. / Susac, L. / Trowitzsch, S. / Thomas, C. / Tampe, R.
Funding supportEuropean Union, 2items
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, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 20, 2022Provider: repository / Type: Initial release
Revision 1.1Aug 24, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Beta-2-microglobulin
T: Tapasin
E: Protein disulfide-isomerase A3
M: HLA class I histocompatibility antigen, A-3 alpha chain
C: Calreticulin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)198,5597
Polymers196,7375
Non-polymers1,8222
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area13480 Å2
ΔGint-16 kcal/mol
Surface area71610 Å2
MethodPISA

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Components

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Protein , 5 types, 5 molecules BTEMC

#1: Protein Beta-2-microglobulin


Mass: 11748.160 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P61769
#2: Protein Tapasin / TPSN / NGS-17 / TAP-associated protein / TAP-binding protein


Mass: 45761.184 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: O15533
#3: Protein Protein disulfide-isomerase A3 / 58 kDa glucose-regulated protein / 58 kDa microsomal protein / p58 / Disulfide isomerase ER-60 / ...58 kDa glucose-regulated protein / 58 kDa microsomal protein / p58 / Disulfide isomerase ER-60 / Endoplasmic reticulum resident protein 57 / ERp57 / Endoplasmic reticulum resident protein 60 / ERp60


Mass: 54341.102 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P30101, protein disulfide-isomerase
#4: Protein HLA class I histocompatibility antigen, A-3 alpha chain / MHC class I antigen A*3


Mass: 38363.535 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P04439
#5: Protein Calreticulin / CRP55 / Calregulin / Endoplasmic reticulum resident protein 60 / ERp60 / HACBP / grp60


Mass: 46523.211 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P27797

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Sugars , 2 types, 2 molecules

#6: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#7: Polysaccharide alpha-D-glucopyranose-(1-3)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D- ...alpha-D-glucopyranose-(1-3)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1235.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpa1-3DManpa1-2DManpa1-2DManpa1-3DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/4,7,6/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5][a2122h-1a_1-5]/1-1-2-3-3-3-4/a4-b1_b4-c1_c3-d1_d2-e1_e2-f1_f3-g1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{[(2+1)][a-D-Manp]{[(3+1)][a-D-Glcp]{}}}}}}}LINUCSPDB-CARE

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Details

Has ligand of interestY

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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: editing module of peptide-loading complex / Type: COMPLEX / Entity ID: #1-#5 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 68 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionDetails: Patch CTF / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.73 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 97952 / Symmetry type: POINT

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