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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-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 / TAP2 binding / TAP1 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 / TAP2 binding / TAP1 binding / cytolytic granule / positive regulation of dendritic cell chemotaxis / protein disulfide-isomerase / Assembly of Viral Components at the Budding Site / ATF6 (ATF6-alpha) activates chaperone genes / negative regulation of trophoblast cell migration / cortical granule / nuclear receptor-mediated glucocorticoid signaling pathway / cellular response to electrical stimulus / complement component C1q complex binding / regulation of meiotic nuclear division / negative regulation of retinoic acid receptor signaling pathway / response to glycoside / endoplasmic reticulum quality control compartment / sequestering of calcium ion / sarcoplasmic reticulum lumen / protein folding in endoplasmic reticulum / hormone binding / disulfide oxidoreductase activity / negative regulation of intracellular steroid hormone receptor signaling pathway / regulation of protein complex stability / nuclear export signal receptor activity / phospholipase C activity / cardiac muscle cell differentiation / molecular sequestering activity / retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum / cellular response to interleukin-7 / positive regulation of extrinsic apoptotic signaling pathway / Scavenging by Class A Receptors / Scavenging by Class F Receptors / protein maturation by protein folding / cortical actin cytoskeleton organization / positive regulation of memory T cell activation / T cell mediated cytotoxicity directed against tumor cell target / 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 / protein disulfide isomerase activity / MHC class I protein binding / antigen processing and presentation of exogenous peptide antigen via MHC class I / response to testosterone / endoplasmic reticulum exit site / antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-dependent / protein-disulfide reductase activity / TAP binding / protection from natural killer cell mediated cytotoxicity / protein localization to nucleus / negative regulation of neuron differentiation / positive regulation of cell cycle / beta-2-microglobulin binding / smooth endoplasmic reticulum / T cell receptor binding / phagocytic vesicle / detection of bacterium / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of phagocytosis / ERAD pathway / extrinsic apoptotic signaling pathway / endocytic vesicle lumen / protein folding chaperone / endoplasmic reticulum-Golgi intermediate compartment membrane / response to endoplasmic reticulum stress / protein export from nucleus / positive regulation of endothelial cell migration / 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 / negative regulation of receptor binding / DAP12 interactions / 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 / cellular response to iron ion / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / lumenal side of endoplasmic reticulum membrane / 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 / peptide antigen assembly with MHC class I protein complex / ER to Golgi transport vesicle membrane / 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 / : / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Concanavalin A-like lectin/glucanase domain superfamily / 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
Revision 3.0May 15, 2024Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_validate_close_contact / struct_conn
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_atom_id / _atom_site.auth_comp_id / _atom_site.auth_seq_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.type_symbol / _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_entity_branch_link.atom_id_1 / _pdbx_entity_branch_link.atom_id_2 / _pdbx_entity_branch_link.comp_id_1 / _pdbx_entity_branch_link.comp_id_2 / _pdbx_entity_branch_link.entity_branch_list_num_1 / _pdbx_entity_branch_link.entity_branch_list_num_2 / _pdbx_entity_branch_link.leaving_atom_id_1 / _pdbx_entity_branch_link.leaving_atom_id_2 / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_label_atom_id

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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
Water00
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


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
WURCS=2.0/2,4,3/[a1122h-1a_1-5][a2122h-1b_1-5]/1-1-1-2/a2-b1_b2-c1_c3-d1WURCSPDB2Glycan 1.1.0
[][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 FIELD
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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