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- EMDB-43488: Cryo-EM structure of human invariant chain in complex with HLA-DR15 -

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Basic information

Entry
Database: EMDB / ID: EMD-43488
TitleCryo-EM structure of human invariant chain in complex with HLA-DR15
Map dataSharpen map after cryoSPRARC DeepEhancer
Sample
  • Complex: Trimeric complex of invariant chain associated with HLA-DRA1 and HLA-DRB1
    • Protein or peptide: HLA class II histocompatibility antigen, DR alpha chain
    • Protein or peptide: HLA class II histocompatibility antigen, DRB1 beta chain
    • Protein or peptide: HLA class II histocompatibility antigen gamma chain
KeywordsAntigen presentation / membrane protein / trimeric complex / IMMUNE SYSTEM
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 / regulation of interleukin-4 production / regulation of interleukin-10 production / myeloid dendritic cell antigen processing and presentation / antigen processing and presentation of endogenous peptide antigen via MHC class II / T cell activation involved in immune response / autolysosome membrane / positive regulation of type 2 immune response / positive regulation of prostaglandin biosynthetic process / regulation of T-helper cell differentiation / T cell selection / positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation / negative thymic T cell selection / negative regulation of viral entry into host cell / MHC class II receptor activity / positive regulation of T cell mediated immune response to tumor cell / MHC class II protein binding / positive regulation of CD4-positive, alpha-beta T cell activation / antigen processing and presentation of peptide or polysaccharide antigen via MHC class II / negative regulation of mature B cell apoptotic process / positive regulation of memory T cell differentiation / positive thymic T cell selection / positive regulation of kinase activity / CD4 receptor binding / positive regulation of monocyte differentiation / inflammatory response to antigenic stimulus / 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 / intermediate filament / regulation of macrophage activation / polysaccharide binding / T-helper 1 type immune response / 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 / response to type II interferon / positive regulation of insulin secretion involved in cellular response to glucose stimulus / antigen processing and presentation / cytokine binding / negative regulation of DNA damage response, signal transduction by p53 class mediator / chaperone cofactor-dependent protein refolding / macrophage differentiation / negative regulation of type II interferon production / humoral immune response / Generation of second messenger molecules / immunological synapse / PD-1 signaling / epidermis development / immunoglobulin mediated immune response / T cell receptor binding / negative regulation of T cell proliferation / detection of bacterium / positive regulation of chemokine production / positive regulation of B cell proliferation / 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 / negative regulation of inflammatory response to antigenic stimulus / protein tetramerization / intracellular protein transport / clathrin-coated endocytic vesicle membrane / ER to Golgi transport vesicle membrane / structural constituent of cytoskeleton / cognition / peptide antigen assembly with MHC class II protein complex / MHC class II protein complex / positive regulation of interleukin-6 production / positive regulation of T cell mediated cytotoxicity / 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
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, DR alpha chain / HLA class II histocompatibility antigen, DRB1 beta chain / HLA class II histocompatibility antigen gamma chain
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.03 Å
AuthorsWang N / Caveney NA / Jude KM / Garcia KC
Funding support United States, 1 items
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 22, 2024-
Header (metadata) releaseMay 8, 2024-
Map releaseMay 8, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

Downloads & links

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Map

FileDownload / File: emd_43488.map.gz / Format: CCP4 / Size: 343 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpen map after cryoSPRARC DeepEhancer
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 448 pix.
= 292.544 Å
0.65 Å/pix.
x 448 pix.
= 292.544 Å
0.65 Å/pix.
x 448 pix.
= 292.544 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.653 Å
Density
Contour LevelBy AUTHOR: 0.00315
Minimum - Maximum-0.023776274 - 2.5544782
Average (Standard dev.)0.0009704265 (±0.021012973)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions448448448
Spacing448448448
CellA=B=C: 292.544 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_43488_msk_1.map
Projections & Slices
AxesZYX

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Density Histograms

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Half map: #2

Fileemd_43488_half_map_1.map
Projections & Slices
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Half map: #1

Fileemd_43488_half_map_2.map
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Sample components

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Entire : Trimeric complex of invariant chain associated with HLA-DRA1 and ...

EntireName: Trimeric complex of invariant chain associated with HLA-DRA1 and HLA-DRB1
Components
  • Complex: Trimeric complex of invariant chain associated with HLA-DRA1 and HLA-DRB1
    • Protein or peptide: HLA class II histocompatibility antigen, DR alpha chain
    • Protein or peptide: HLA class II histocompatibility antigen, DRB1 beta chain
    • Protein or peptide: HLA class II histocompatibility antigen gamma chain

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Supramolecule #1: Trimeric complex of invariant chain associated with HLA-DRA1 and ...

SupramoleculeName: Trimeric complex of invariant chain associated with HLA-DRA1 and HLA-DRB1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 330 KDa

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Macromolecule #1: HLA class II histocompatibility antigen, DR alpha chain

MacromoleculeName: HLA class II histocompatibility antigen, DR alpha chain
type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 32.418971 KDa
Recombinant expressionOrganism: Mammalia (mammals)
SequenceString: MAISGVPVLG FFIIAVLMSA QESWAIKEEH VIIQAEFYLN PDQSGEFMFD FDGDEIFHVD MAKKETVWRL EEFGRFASFE AQGALANIA VDKANLEIMT KRSNYTPITN VPPEVTVLTN SPVELREPNV LICFIDKFTP PVVNVTWLRN GKPVTTGVSE T VFLPREDH ...String:
MAISGVPVLG FFIIAVLMSA QESWAIKEEH VIIQAEFYLN PDQSGEFMFD FDGDEIFHVD MAKKETVWRL EEFGRFASFE AQGALANIA VDKANLEIMT KRSNYTPITN VPPEVTVLTN SPVELREPNV LICFIDKFTP PVVNVTWLRN GKPVTTGVSE T VFLPREDH LFRKFHYLPF LPSTEDVYDC RVEHWGLDEP LLKHWEFDAP SPLPETTENV VCALGLTVGL VGIIIGTIFI IK GLRKSNA AERRGPLAAA LEVLFQGPGA AEDQVDPRLI DGKHHHHHHH H

UniProtKB: HLA class II histocompatibility antigen, DR alpha chain

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Macromolecule #2: HLA class II histocompatibility antigen, DRB1 beta chain

MacromoleculeName: HLA class II histocompatibility antigen, DRB1 beta chain
type: protein_or_peptide / ID: 2 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 33.768199 KDa
Recombinant expressionOrganism: Mammalia (mammals)
SequenceString: MVCLKLPGGS CMTALTVTLM VLSSPLALSG DTRPRFLWQP KRECHFFNGT ERVRFLDRYF YNQEESVRFD SDVGEFRAVT ELGRPDAEY WNSQKDILEQ ARAAVDTYCR HNYGVVESFT VQRRVQPKVT VYPSKTQPLQ HHNLLVCSVS GFYPGSIEVR W FLNGQEEK ...String:
MVCLKLPGGS CMTALTVTLM VLSSPLALSG DTRPRFLWQP KRECHFFNGT ERVRFLDRYF YNQEESVRFD SDVGEFRAVT ELGRPDAEY WNSQKDILEQ ARAAVDTYCR HNYGVVESFT VQRRVQPKVT VYPSKTQPLQ HHNLLVCSVS GFYPGSIEVR W FLNGQEEK AGMVSTGLIQ NGDWTFQTLV MLETVPRSGE VYTCQVEHPS VTSPLTVEWR ARSESAQSKM LSGVGGFVLG LL FLGAGLF IYFRNQKGHS GLQPTGFLSA AALEVLFQGP GAAEDQVDPR LIDGKHHHHH HHH

UniProtKB: HLA class II histocompatibility antigen, DRB1 beta chain

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Macromolecule #3: HLA class II histocompatibility antigen gamma chain

MacromoleculeName: HLA class II histocompatibility antigen gamma chain / type: protein_or_peptide / ID: 3 / Number of copies: 3 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 34.901906 KDa
Recombinant expressionOrganism: Mammalia (mammals)
SequenceString: MDYKDDDDAG TSRHRRRSRS CREDQKPVMD DQRDLISNNE QLPMLGRRPG APESKCSRGA LYTGFSILVT LLLAGQATTA YFLYQQQGR LDKLTVTSQN LQLENLRMKL PKPPKPVSKM RMATPLLMQA LPMGALPQGP MQNATKYGNM TEDHVMHLLQ N ADPLKVYP ...String:
MDYKDDDDAG TSRHRRRSRS CREDQKPVMD DQRDLISNNE QLPMLGRRPG APESKCSRGA LYTGFSILVT LLLAGQATTA YFLYQQQGR LDKLTVTSQN LQLENLRMKL PKPPKPVSKM RMATPLLMQA LPMGALPQGP MQNATKYGNM TEDHVMHLLQ N ADPLKVYP PLKGSFPENL RHLKNTMETI DWKVFESWMH HWLLFEMSRH SLEQKPTDAP PKVLTKCQEE VSHIPAVHPG SF RPKCDEN GNYLPLQCYG SIGYCWCVFP NGTEVPNTRS RGHHNCSESL ELEDPSSGLG VTKQDLGPVP M

UniProtKB: HLA class II histocompatibility antigen gamma chain

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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

Concentration5 mg/mL
BufferpH: 8
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec. / Pretreatment - Atmosphere: AIR
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 281 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 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: PDB ENTRY
PDB model - PDB ID:
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.03 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 391922
Initial angle assignmentType: NOT APPLICABLE
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementProtocol: AB INITIO MODEL
Output model

PDB-8vrw:
Cryo-EM structure of human invariant chain in complex with HLA-DR15

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