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- PDB-7y0j: Cryo-EM structure of human IgM-Fc in complex with the J chain and... -

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Basic information

Entry
Database: PDB / ID: 7y0j
TitleCryo-EM structure of human IgM-Fc in complex with the J chain and the P. falciparum TM284VAR1
Components
  • Erythrocyte membrane protein 2 variant TM284var1Red blood cell
  • Immunoglobulin J chain
  • Immunoglobulin heavy constant mu
KeywordsIMMUNE SYSTEM / Complex / antibody
Function / homology
Function and homology information


hexameric IgM immunoglobulin complex / dimeric IgA immunoglobulin complex / IgM B cell receptor complex / secretory dimeric IgA immunoglobulin complex / pentameric IgM immunoglobulin complex / monomeric IgA immunoglobulin complex / secretory IgA immunoglobulin complex / IgA binding / glomerular filtration / pre-B cell allelic exclusion ...hexameric IgM immunoglobulin complex / dimeric IgA immunoglobulin complex / IgM B cell receptor complex / secretory dimeric IgA immunoglobulin complex / pentameric IgM immunoglobulin complex / monomeric IgA immunoglobulin complex / secretory IgA immunoglobulin complex / IgA binding / glomerular filtration / pre-B cell allelic exclusion / IgM immunoglobulin complex / CD22 mediated BCR regulation / immunoglobulin complex, circulating / immunoglobulin receptor binding / positive regulation of respiratory burst / humoral immune response / Scavenging of heme from plasma / complement activation, classical pathway / antigen binding / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Cell surface interactions at the vascular wall / B cell receptor signaling pathway / protein-macromolecule adaptor activity / antibacterial humoral response / protein-containing complex assembly / blood microparticle / defense response to Gram-negative bacterium / Potential therapeutics for SARS / adaptive immune response / host cell surface receptor binding / immune response / innate immune response / cell surface / protein homodimerization activity / extracellular space / extracellular exosome / extracellular region / membrane / plasma membrane
Similarity search - Function
Cysteine-rich interdomain region 1 gamma / Cysteine-Rich Interdomain Region 1 gamma / Duffy-binding-like domain / PFEMP1 DBL domain / Plasmodium falciparum erythrocyte membrane protein 1, acidic terminal segment superfamily / Immunoglobulin J chain / Plasmodium falciparum erythrocyte membrane protein 1, acidic terminal segment / Immunoglobulin J chain / acidic terminal segments, variant surface antigen of PfEMP1 / Duffy-antigen binding ...Cysteine-rich interdomain region 1 gamma / Cysteine-Rich Interdomain Region 1 gamma / Duffy-binding-like domain / PFEMP1 DBL domain / Plasmodium falciparum erythrocyte membrane protein 1, acidic terminal segment superfamily / Immunoglobulin J chain / Plasmodium falciparum erythrocyte membrane protein 1, acidic terminal segment / Immunoglobulin J chain / acidic terminal segments, variant surface antigen of PfEMP1 / Duffy-antigen binding / Duffy-antigen binding superfamily / Duffy binding domain / 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
Erythrocyte membrane protein 2 variant TM284var1 / Immunoglobulin J chain / Immunoglobulin heavy constant mu
Similarity search - Component
Biological speciesPlasmodium falciparum (malaria parasite P. falciparum)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.62 Å
AuthorsJi, C. / Xiao, J.
Funding support China, 1items
OrganizationGrant numberCountry
National Science Foundation (NSF, China) China
CitationJournal: Nat Commun / Year: 2023
Title: Plasmodium falciparum has evolved multiple mechanisms to hijack human immunoglobulin M.
Authors: Chenggong Ji / Hao Shen / Chen Su / Yaxin Li / Shihua Chen / Thomas H Sharp / Junyu Xiao /
Abstract: Plasmodium falciparum causes the most severe malaria in humans. Immunoglobulin M (IgM) serves as the first line of humoral defense against infection and potently activates the complement pathway to ...Plasmodium falciparum causes the most severe malaria in humans. Immunoglobulin M (IgM) serves as the first line of humoral defense against infection and potently activates the complement pathway to facilitate P. falciparum clearance. A number of P. falciparum proteins bind IgM, leading to immune evasion and severe disease. However, the underlying molecular mechanisms remain unknown. Here, using high-resolution cryo-electron microscopy, we delineate how P. falciparum proteins VAR2CSA, TM284VAR1, DBLMSP, and DBLMSP2 target IgM. Each protein binds IgM in a different manner, and together they present a variety of Duffy-binding-like domain-IgM interaction modes. We further show that these proteins interfere directly with IgM-mediated complement activation in vitro, with VAR2CSA exhibiting the most potent inhibitory effect. These results underscore the importance of IgM for human adaptation of P. falciparum and provide critical insights into its immune evasion mechanism.
History
DepositionJun 5, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 5, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / 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.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2May 8, 2024Group: Database references / Category: citation
Item: _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
M: Erythrocyte membrane protein 2 variant TM284var1
A: Immunoglobulin heavy constant mu
B: Immunoglobulin heavy constant mu
C: Immunoglobulin heavy constant mu
D: Immunoglobulin heavy constant mu
E: Immunoglobulin heavy constant mu
F: Immunoglobulin heavy constant mu
G: Immunoglobulin heavy constant mu
H: Immunoglobulin heavy constant mu
K: Immunoglobulin heavy constant mu
L: Immunoglobulin heavy constant mu
J: Immunoglobulin J chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)714,38323
Polymers711,74612
Non-polymers2,63611
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Erythrocyte membrane protein 2 variant TM284var1 / Red blood cell


Mass: 277505.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Plasmodium falciparum (malaria parasite P. falciparum)
Production host: Trichoplusia ni (cabbage looper) / References: UniProt: I1X0L2
#2: Protein
Immunoglobulin heavy constant mu / Ig mu chain C region / Ig mu chain C region BOT / Ig mu chain C region GAL / Ig mu chain C region OU


Mass: 41875.766 Da / Num. of mol.: 10
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IGHM / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P01871
#3: Protein Immunoglobulin J chain / Joining chain of multimeric IgA and IgM


Mass: 15483.329 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: JCHAIN, IGCJ, IGJ / Cell line (production host): HEK293 / Production host: Homo sapiens (human) / References: UniProt: P01591
#4: 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
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#5: 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C8H15NO6
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 interestN

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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

Component
IDNameTypeEntity IDParent-IDSource
1Ternary complex of human IgM-Fc in complex with the J chain and the P. falciparum TM284VAR1COMPLEX#1-#30RECOMBINANT
2TM284VAR1COMPLEX#11RECOMBINANT
3Immunoglobulin heavy constant muCOMPLEX#21RECOMBINANT
4Immunoglobulin J chainCOMPLEX#31RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Plasmodium falciparum (malaria parasite P. falciparum)5833
32Homo sapiens (human)9606
43Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
21Trichoplusia ni (cabbage looper)7111
32Homo sapiens (human)9606HEK293
43Homo sapiens (human)9606HEK293
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 FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 59.74 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.1_4122: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.62 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 849826 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00321224
ELECTRON MICROSCOPYf_angle_d0.65429000
ELECTRON MICROSCOPYf_dihedral_angle_d5.5922882
ELECTRON MICROSCOPYf_chiral_restr0.0473407
ELECTRON MICROSCOPYf_plane_restr0.0063693

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