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- PDB-8vsp: Cryo-EM structure of human invariant chain in complex with HLA-DQ -

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Basic information

Entry
Database: PDB / ID: 8vsp
TitleCryo-EM structure of human invariant chain in complex with HLA-DQ
Components
  • HLA class II histocompatibility antigen gamma chain
  • HLA class II histocompatibility antigen, DQ alpha 1 chain
  • HLA class II histocompatibility antigen, DQ beta 1 chain
KeywordsIMMUNE SYSTEM / Antigen presentation / membrane protein / trimeric complex
Function / homology
Function and homology information


negative regulation of peptide secretion / macrophage migration inhibitory factor signaling pathway / NOS2-CD74 complex / MHC class II protein binding, via antigen binding groove / antigen processing and presentation of endogenous antigen / positive regulation of dendritic cell antigen processing and presentation / negative regulation of T cell differentiation / macrophage migration inhibitory factor binding / positive regulation of macrophage migration inhibitory factor signaling pathway / protein trimerization ...negative regulation of peptide secretion / macrophage migration inhibitory factor signaling pathway / NOS2-CD74 complex / MHC class II protein binding, via antigen binding groove / antigen processing and presentation of endogenous antigen / positive regulation of dendritic cell antigen processing and presentation / negative regulation of T cell differentiation / macrophage migration inhibitory factor binding / positive regulation of macrophage migration inhibitory factor signaling pathway / protein trimerization / macrophage migration inhibitory factor receptor complex / positive regulation of cytokine-mediated signaling pathway / T cell activation involved in immune response / positive regulation of type 2 immune response / positive regulation of prostaglandin biosynthetic process / T cell selection / negative thymic T cell selection / negative regulation of viral entry into host cell / MHC class II receptor activity / MHC class II protein binding / negative regulation of mature B cell apoptotic process / positive thymic T cell selection / positive regulation of kinase activity / CD4 receptor binding / positive regulation of monocyte differentiation / vacuole / positive regulation of chemokine (C-X-C motif) ligand 2 production / positive regulation of neutrophil chemotaxis / cytokine receptor activity / prostaglandin biosynthetic process / positive regulation of macrophage cytokine production / positive regulation of T cell differentiation / regulation of macrophage activation / negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / transport vesicle membrane / nitric-oxide synthase binding / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / cytokine binding / response to type II interferon / antigen processing and presentation / negative regulation of DNA damage response, signal transduction by p53 class mediator / chaperone cofactor-dependent protein refolding / humoral immune response / Generation of second messenger molecules / PD-1 signaling / immunoglobulin mediated immune response / positive regulation of B cell proliferation / positive regulation of chemokine production / protein folding chaperone / MHC class II antigen presentation / multivesicular body / lysosomal lumen / trans-Golgi network membrane / negative regulation of cell migration / positive regulation of interleukin-8 production / Cell surface interactions at the vascular wall / lumenal side of endoplasmic reticulum membrane / intracellular protein transport / clathrin-coated endocytic vesicle membrane / ER to Golgi transport vesicle membrane / peptide antigen assembly with MHC class II protein complex / MHC class II protein complex / positive regulation of interleukin-6 production / peptide antigen binding / antigen processing and presentation of exogenous peptide antigen via MHC class II / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of immune response / Interferon gamma signaling / positive regulation of fibroblast proliferation / endocytic vesicle membrane / positive regulation of T cell activation / late endosome / Downstream TCR signaling / MHC class II protein complex binding / late endosome membrane / T cell receptor signaling pathway / amyloid-beta binding / protein-containing complex assembly / positive regulation of canonical NF-kappaB signal transduction / adaptive immune response / positive regulation of MAPK cascade / lysosome / positive regulation of ERK1 and ERK2 cascade / positive regulation of viral entry into host cell / protein stabilization / immune response / positive regulation of protein phosphorylation / lysosomal membrane / Golgi membrane / external side of plasma membrane / positive regulation of gene expression / negative regulation of apoptotic process / positive regulation of DNA-templated transcription / cell surface / protein-containing complex / extracellular exosome / identical protein binding / membrane / nucleus
Similarity search - Function
MHC class II-associated invariant chain, trimerisation / MHC class II-associated invariant chain/CLIP, MHC II-interacting / MHC class II-associated invariant chain / MHC class II-associated invariant chain, trimerisation domain superfamily / HLA class II histocompatibility antigen, gamma subunit / Class II MHC-associated invariant chain trimerisation domain / CLIP, MHC2 interacting / : / Thyroglobulin type-1 repeat signature. / Thyroglobulin type-1 ...MHC class II-associated invariant chain, trimerisation / MHC class II-associated invariant chain/CLIP, MHC II-interacting / MHC class II-associated invariant chain / MHC class II-associated invariant chain, trimerisation domain superfamily / HLA class II histocompatibility antigen, gamma subunit / Class II MHC-associated invariant chain trimerisation domain / CLIP, MHC2 interacting / : / Thyroglobulin type-1 repeat signature. / Thyroglobulin type-1 / Thyroglobulin type-1 superfamily / Thyroglobulin type-1 repeat / Thyroglobulin type-1 domain profile. / Thyroglobulin type I repeats. / MHC class II, beta chain, N-terminal / Class II histocompatibility antigen, beta domain / Class II histocompatibility antigen, beta domain / MHC class II, alpha chain, N-terminal / Class II histocompatibility antigen, alpha domain / Class II histocompatibility antigen, alpha domain / MHC class II, alpha/beta chain, N-terminal / 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 / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
HLA class II histocompatibility antigen, DQ alpha 1 chain / HLA class II histocompatibility antigen, DQ beta 1 chain / HLA class II histocompatibility antigen gamma chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.12 Å
AuthorsWang, N. / Caveney, N.A. / Jude, K.M. / Garcia, K.C.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)NIH R01 AI103867 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: Structural insights into human MHC-II association with invariant chain.
Authors: Nan Wang / Deepa Waghray / Nathanael A Caveney / Kevin M Jude / K Christopher Garcia /
Abstract: The loading of processed peptides on to major histocompatibility complex II (MHC-II) molecules for recognition by T cells is vital to cell-mediated adaptive immunity. As part of this process, MHC-II ...The loading of processed peptides on to major histocompatibility complex II (MHC-II) molecules for recognition by T cells is vital to cell-mediated adaptive immunity. As part of this process, MHC-II associates with the invariant chain (Ii) during biosynthesis in the endoplasmic reticulum to prevent premature peptide loading and to serve as a scaffold for subsequent proteolytic processing into MHC-II-CLIP. Cryo-electron microscopy structures of full-length Human Leukocyte Antigen-DR (HLA-DR) and HLA-DQ complexes associated with Ii, resolved at 3.0 to 3.1 Å, elucidate the trimeric assembly of the HLA/Ii complex and define atomic-level interactions between HLA, Ii transmembrane domains, loop domains, and class II-associated invariant chain peptides (CLIP). Together with previous structures of MHC-II peptide loading intermediates DO and DM, our findings complete the structural path governing class II antigen presentation.
History
DepositionJan 24, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 8, 2024Provider: repository / Type: Initial release
Revision 1.1May 15, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Nov 6, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: HLA class II histocompatibility antigen, DQ alpha 1 chain
B: HLA class II histocompatibility antigen, DQ beta 1 chain
C: HLA class II histocompatibility antigen gamma chain
D: HLA class II histocompatibility antigen, DQ alpha 1 chain
E: HLA class II histocompatibility antigen, DQ beta 1 chain
F: HLA class II histocompatibility antigen gamma chain
G: HLA class II histocompatibility antigen, DQ alpha 1 chain
H: HLA class II histocompatibility antigen, DQ beta 1 chain
I: HLA class II histocompatibility antigen gamma chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)301,56412
Polymers300,9009
Non-polymers6643
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein HLA class II histocompatibility antigen, DQ alpha 1 chain / DC-1 alpha chain / DC-alpha / HLA-DCA / MHC class II DQA1


Mass: 31599.943 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-DQA1 / Production host: Mammalia (mammals) / References: UniProt: P01909
#2: Protein HLA class II histocompatibility antigen, DQ beta 1 chain / MHC class II antigen DQB1


Mass: 33798.309 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-DQB1, HLA-DQB / Production host: Mammalia (mammals) / References: UniProt: P01920
#3: Protein HLA class II histocompatibility antigen gamma chain / HLA-DR antigens-associated invariant chain / Ia antigen-associated invariant chain / Ii


Mass: 34901.906 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD74, DHLAG / Production host: Mammalia (mammals) / References: UniProt: P04233
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestY
Has protein modificationY

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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: Trimeric complex of invariant chain associated with HLA-DQ alpha and beta
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Molecular weightValue: 0.33 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Mammalia (mammals)
Buffer solutionpH: 8
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 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 / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.12 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 421582 / Symmetry type: POINT
Atomic model buildingProtocol: AB INITIO MODEL

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