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- PDB-6eny: Structure of the human PLC editing module -

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Basic information

Entry
Database: PDB / ID: 6eny
TitleStructure of the human PLC editing module
Components
  • Beta-2-microglobulinBeta-2 microglobulin
  • Calreticulin
  • HLA class I histocompatibility antigen, A-3 alpha chain
  • Protein disulfide-isomerase A3
  • Tapasin
KeywordsIMMUNE SYSTEM / adaptive immunity / antigen processing / chaperone / MHC class 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 / cytolytic granule / protein disulfide-isomerase / Assembly of Viral Components at the Budding Site / cortical granule / positive regulation of dendritic cell chemotaxis ...MHC class Ib protein complex assembly / peptide antigen stabilization / Tapasin-ERp57 complex / Calnexin/calreticulin cycle / MHC class I protein complex binding / cytolytic granule / protein disulfide-isomerase / Assembly of Viral Components at the Budding Site / cortical granule / positive regulation of dendritic cell chemotaxis / negative regulation of trophoblast cell migration / ATF6 (ATF6-alpha) activates chaperone genes / negative regulation of retinoic acid receptor signaling pathway / complement component C1q complex binding / cellular response to electrical stimulus / intracellular glucocorticoid receptor signaling pathway / endoplasmic reticulum quality control compartment / sequestering of calcium ion / regulation of meiotic nuclear division / response to glycoside / sarcoplasmic reticulum lumen / protein folding in endoplasmic reticulum / hormone binding / disulfide oxidoreductase activity / nuclear export signal receptor activity / negative regulation of intracellular steroid hormone receptor signaling pathway / regulation of protein complex stability / cardiac muscle cell differentiation / molecular sequestering activity / phospholipase C activity / TAP1 binding / TAP2 binding / retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum / Scavenging by Class A Receptors / cellular response to interleukin-7 / positive regulation of extrinsic apoptotic signaling pathway / protein maturation by protein folding / Scavenging by Class F Receptors / cortical actin cytoskeleton organization / nuclear androgen receptor binding / response to testosterone / protein disulfide isomerase activity / cellular response to lithium ion / smooth endoplasmic reticulum / T cell mediated cytotoxicity directed against tumor cell target / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-dependent / positive regulation of memory T cell activation / TAP complex binding / protein localization to nucleus / antigen processing and presentation of exogenous peptide antigen via MHC class I / Golgi medial cisterna / negative regulation of neuron differentiation / protein-disulfide reductase activity / 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 / CD8 receptor binding / MHC class I protein binding / endoplasmic reticulum exit site / beta-2-microglobulin binding / positive regulation of cell cycle / positive regulation of phagocytosis / phagocytic vesicle / : / positive regulation of substrate adhesion-dependent cell spreading / protein folding chaperone / TAP binding / extrinsic apoptotic signaling pathway / endocytic vesicle lumen / protection from natural killer cell mediated cytotoxicity / 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 / detection of bacterium / protein export from nucleus / endoplasmic reticulum-Golgi intermediate compartment membrane / response to endoplasmic reticulum stress / T cell receptor binding / positive regulation of endothelial cell migration / acrosomal vesicle / positive regulation of ferrous iron binding / positive regulation of transferrin receptor binding / early endosome lumen / positive regulation of receptor binding / Nef mediated downregulation of MHC class I complex cell surface expression / DAP12 interactions / negative regulation of receptor binding / lumenal side of endoplasmic reticulum membrane / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / peptide binding / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / cellular response to iron(III) ion / negative regulation of forebrain neuron differentiation / ER to Golgi transport vesicle membrane / peptide antigen assembly with MHC class I protein complex / response to molecule of bacterial origin / regulation of erythrocyte differentiation / regulation of iron ion transport / MHC class I peptide loading complex / intracellular calcium ion homeostasis
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: 5.8 Å
AuthorsTrowitzsch, S. / Januliene, D. / Blees, A. / Moeller, A. / Tampe, R.
Funding support Germany, 2items
OrganizationGrant numberCountry
German Research FoundationSFB 807 Germany
German Research FoundationGRK 1986 Germany
CitationJournal: Nature / Year: 2017
Title: Structure of the human MHC-I peptide-loading complex.
Authors: Andreas Blees / Dovile Januliene / Tommy Hofmann / Nicole Koller / Carla Schmidt / Simon Trowitzsch / Arne Moeller / Robert Tampé /
Abstract: The peptide-loading complex (PLC) is a transient, multisubunit membrane complex in the endoplasmic reticulum that is essential for establishing a hierarchical immune response. The PLC coordinates ...The peptide-loading complex (PLC) is a transient, multisubunit membrane complex in the endoplasmic reticulum that is essential for establishing a hierarchical immune response. The PLC coordinates peptide translocation into the endoplasmic reticulum with loading and editing of major histocompatibility complex class I (MHC-I) molecules. After final proofreading in the PLC, stable peptide-MHC-I complexes are released to the cell surface to evoke a T-cell response against infected or malignant cells. Sampling of different MHC-I allomorphs requires the precise coordination of seven different subunits in a single macromolecular assembly, including the transporter associated with antigen processing (TAP1 and TAP2, jointly referred to as TAP), the oxidoreductase ERp57, the MHC-I heterodimer, and the chaperones tapasin and calreticulin. The molecular organization of and mechanistic events that take place in the PLC are unknown owing to the heterogeneous composition and intrinsically dynamic nature of the complex. Here, we isolate human PLC from Burkitt's lymphoma cells using an engineered viral inhibitor as bait and determine the structure of native PLC by electron cryo-microscopy. Two endoplasmic reticulum-resident editing modules composed of tapasin, calreticulin, ERp57, and MHC-I are centred around TAP in a pseudo-symmetric orientation. A multivalent chaperone network within and across the editing modules establishes the proofreading function at two lateral binding platforms for MHC-I molecules. The lectin-like domain of calreticulin senses the MHC-I glycan, whereas the P domain reaches over the MHC-I peptide-binding pocket towards ERp57. This arrangement allows tapasin to facilitate peptide editing by clamping MHC-I. The translocation pathway of TAP opens out into a large endoplasmic reticulum lumenal cavity, confined by the membrane entry points of tapasin and MHC-I. Two lateral windows channel the antigenic peptides to MHC-I. Structures of PLC captured at distinct assembly states provide mechanistic insight into the recruitment and release of MHC-I. Our work defines the molecular symbiosis of an ABC transporter and an endoplasmic reticulum chaperone network in MHC-I assembly and provides insight into the onset of the adaptive immune response.
History
DepositionOct 7, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 29, 2017Provider: repository / Type: Initial release
Revision 1.1Dec 6, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 2.0Jul 29, 2020Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_branch_scheme / pdbx_chem_comp_identifier / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_struct_assembly_gen / pdbx_unobs_or_zero_occ_atoms / pdbx_validate_close_contact / struct_asym / struct_conn / struct_site / struct_site_gen
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_asym_id / _atom_site.auth_atom_id / _atom_site.auth_seq_id / _atom_site.label_asym_id / _atom_site.label_atom_id / _atom_site.label_entity_id / _atom_site.type_symbol / _chem_comp.name / _chem_comp.type / _pdbx_struct_assembly_gen.asym_id_list
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)197,8127
Polymers196,7215
Non-polymers1,0912
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: cross-linking, gel filtration, native gel electrophoresis, mass spectrometry, microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 5 types, 5 molecules BCDFG

#1: Protein Beta-2-microglobulin / 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: 46507.145 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 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][b-D-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#7: Polysaccharide beta-D-glucopyranose-(1-3)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose


Type: oligosaccharide / Mass: 666.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpb1-3DManpa1-2DManpa1-2DManpa1-ROHGlycam Condensed SequenceGMML 1.0
[][a-D-Manp]{[(2+1)][a-D-Manp]{[(2+1)][a-D-Manp]{[(3+1)][b-D-Glcp]{}}}}LINUCSPDB-CARE

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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: Protein Complex / Type: COMPLEX / Entity ID: #1-#5 / Source: NATURAL
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: C-flat-2/2
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 K

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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 FIELDBright-field microscopy
Image recordingElectron dose: 55 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

EM software
IDNameVersionCategory
2Gautomatchparticle selection
3EPUimage acquisition
5GctfCTF correction
8Cootmodel fitting
9Flex-EMmodel fitting
11RELION2.1initial Euler assignment
14FREALIGNX3D reconstruction
15PHENIXmodel refinement
CTF correctionDetails: CTF correction was performed internally in Relion and Frealign
Type: NONE
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 5.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 141078 / Symmetry type: POINT
RefinementHighest resolution: 5.8 Å

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