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- EMDB-33547: Cryo-EM structure of human IgM-Fc in complex with the J chain and... -

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Entry
Database: EMDB / ID: EMD-33547
TitleCryo-EM structure of human IgM-Fc in complex with the J chain and the P. falciparum TM284VAR1
Map data
Sample
  • Complex: Ternary complex of human IgM-Fc in complex with the J chain and the P. falciparum TM284VAR1
    • Complex: TM284VAR1
      • Protein or peptide: Erythrocyte membrane protein 2 variant TM284var1
    • Complex: Immunoglobulin heavy constant mu
      • Protein or peptide: Immunoglobulin heavy constant mu
    • Complex: Immunoglobulin J chain
      • Protein or peptide: Immunoglobulin J chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsComplex / antibody / IMMUNE SYSTEM
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 / pre-B cell allelic exclusion / IgM immunoglobulin complex ...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 / pre-B cell allelic exclusion / IgM immunoglobulin complex / glomerular filtration / 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 / antibacterial humoral response / protein-macromolecule adaptor activity / protein-containing complex assembly / defense response to Gram-negative bacterium / blood microparticle / adaptive immune response / Potential therapeutics for SARS / 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, C-terminal subdomain / Duffy-binding-like domain / PFEMP1 DBL domain / Immunoglobulin J chain / Plasmodium falciparum erythrocyte membrane protein 1, acidic terminal segment superfamily / Immunoglobulin J chain / Plasmodium falciparum erythrocyte membrane protein 1, acidic terminal segment / acidic terminal segments, variant surface antigen of PfEMP1 ...Cysteine-rich interdomain region 1 gamma / Cysteine-Rich Interdomain Region 1 gamma / Duffy-binding-like domain, C-terminal subdomain / Duffy-binding-like domain / PFEMP1 DBL domain / Immunoglobulin J chain / Plasmodium falciparum erythrocyte membrane protein 1, acidic terminal segment superfamily / Immunoglobulin J chain / Plasmodium falciparum erythrocyte membrane protein 1, acidic terminal segment / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.62 Å
AuthorsJi C / Xiao J
Funding support China, 1 items
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, 2022-
Header (metadata) releaseApr 5, 2023-
Map releaseApr 5, 2023-
UpdateMay 8, 2024-
Current statusMay 8, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33547.png

Downloads & links

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Map

FileDownload / File: emd_33547.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 400 pix.
= 340. Å		0.85 Å/pix.
x 400 pix.
= 340. Å		0.85 Å/pix.
x 400 pix.
= 340. Å

Surface

Projections

Slices (1/3)

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Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.13
Minimum - Maximum-1.7779211 - 2.7363858
Average (Standard dev.)0.0017329144 (±0.041365303)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 340.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_33547_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_33547_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Ternary complex of human IgM-Fc in complex with the J chain and t...

EntireName: Ternary complex of human IgM-Fc in complex with the J chain and the P. falciparum TM284VAR1
Components
  • Complex: Ternary complex of human IgM-Fc in complex with the J chain and the P. falciparum TM284VAR1
    • Complex: TM284VAR1
      • Protein or peptide: Erythrocyte membrane protein 2 variant TM284var1
    • Complex: Immunoglobulin heavy constant mu
      • Protein or peptide: Immunoglobulin heavy constant mu
    • Complex: Immunoglobulin J chain
      • Protein or peptide: Immunoglobulin J chain
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Ternary complex of human IgM-Fc in complex with the J chain and t...

SupramoleculeName: Ternary complex of human IgM-Fc in complex with the J chain and the P. falciparum TM284VAR1
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Plasmodium falciparum (malaria parasite P. falciparum)

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Supramolecule #2: TM284VAR1

SupramoleculeName: TM284VAR1 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Immunoglobulin heavy constant mu

SupramoleculeName: Immunoglobulin heavy constant mu / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: Immunoglobulin J chain

SupramoleculeName: Immunoglobulin J chain / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3

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Macromolecule #1: Erythrocyte membrane protein 2 variant TM284var1

MacromoleculeName: Erythrocyte membrane protein 2 variant TM284var1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Plasmodium falciparum (malaria parasite P. falciparum)
Molecular weightTheoretical: 277.505219 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MTSKRGNRTV INLSVTDVLE KIALQIYKEE NEKKIPHESE LIGTLWKAQF SDGLSGSFGD VRSGPSNSCN LHHKYYTNIK NGYPPARNP CDGRNEKRFS NEGEAECGSD KIRVIGKGDG TACVPFRRQN MCDKNLEYLI NKNTKTTHDL LGNVLVTAKY E GASIVAKH ...String:
MTSKRGNRTV INLSVTDVLE KIALQIYKEE NEKKIPHESE LIGTLWKAQF SDGLSGSFGD VRSGPSNSCN LHHKYYTNIK NGYPPARNP CDGRNEKRFS NEGEAECGSD KIRVIGKGDG TACVPFRRQN MCDKNLEYLI NKNTKTTHDL LGNVLVTAKY E GASIVAKH PHKDTSEVCT ALARSFADIG DIVRGRDMFL PNKDDKVQKG LREVFKKIHD NLSSSVKPHY KDDGSGNYVK LR EDWWAIN RKEVWNALTC EAPQSVHYFI KTSHGTRGFT SQGKCGRNET NVPTNLDYVP QYLRWFDEWA EEFCRLRNHK LQN VKKECR GENIGDKYCS GDGEDCEKIV RQDYNIRSDF LCPSCKKECT NYKKWIDTKQ GEFNKQKKKY EKEIKKVESN SDTT YDKKV YKILKEMYPL NSEFVATLKE APYCNNNNVD GTIDFNKPDD TFSRSDYCKS CPVFGVICTR GECTEVKEDT CSKMN VKVP KKITNKEDPI NIGILVSDDR VSVIPNELEN VCKDTGLFKG IRKDQRSCNY LCNLDVCDLS HNKNNTHIDK RISIRV LFK RWLEYFFKDY SKLKKKLNSC TNNGEKSICI NKCKKKCECV GKWVEEKRTE WEKVRKRYFS QYNVDDSQKS YTVKSIV NG NVDRSDINNS LDESEDIETL KESDTCYNSD SAKKQKCEKN DVITILIDRL KKKIDDCEKQ HDNRTNQICC DELPESKE D DEDEEEEGKK KKNAKQLEVT NEKKEQEDKN LFQVCQKMKK VITDNNGERI RNQRCNEKTD RKWDCSTNEI PTNHTGACM PPRRISLCIR PLRYLVDNGG KKSIDDYKNA FTECASIETY LLWQKYKRTN GAEDKLKDGE IPNDFLRIMY YTYGDYRDIF LGTDISKNP NIKNISNKVK NILKFKKSMD ESGKNQDENA KVQSSWDEHK RDIWKGMLCG LTYDIQNEKK DILKILNNKY N YPCDLEVF ASKPQFFRWF IEWAEDYCRK YNDEYEKLQT ACSTVDCSKD PTDSEKQKCK NACDNFKTFV EGWKKQYDSQ KN KFNKIKI EANIKNTYKG IENKEAYVFL SEECKGKCDC IKYKTDYDTN ANDPKGFDTP PKEQKDNCEC VLRKKSACEN NEV PKGRTQ SQMTCADLKN ESPSKGNNNT GNNHKETITF SCNKSNLIGL GAQWKKITDD GLYASPRTRQ LCLKHVIDIG RNNT KKNNI TEEEFINVLQ KDAYAEGKLL YMYYNSNGKI SIFQNGEKLK LDDIEKHTHE AMKRSYADYG DLIKGTTKYT QYNDY NKIS DIINVVTKKK NSASINDIYE REEFWEKYRA DVWNAMLCGY KDVSNKTFDG NDDMCNLPNT DKEEEFLRWF KEWNEN FCI TQIKRAEKLK NECNNFNCSS IKSKKDDIKS KCVKACINYK KFVKESKTQY EDQKRTYNER HNKTNKDIPT FLKDNCI HK NCDCISIKFN HKDNWEKSFF ESLDSSDIKN KCECLKLEEE SNTTERYISK EDPQYHPEYK GDGKVNYKYE KGKPKALP S IYPLNCAEKV ADELRMYAEN SLDTNTKLKA KISKSIDTNE QNATNDEIDC NIYNNISNGQ KNTCEHNGNT FHDKDEWDC NKGTNKLYEN DICLPPRRKH MCTKQLENIS TASITTTDDL LKEVLITAVN EGKRLKQQWE KTENEAQKKK HFLCDAMKYS FADLADIIR GTDIWKGNRE QQKIQERLVK IFRNIYDNLE KDEYEKYKYG TKYQNLRSAW WDAHRKKIWN AMTCSAPGDF L FVKRGKGD GSDIEFLTFS EHKKCGHDKE PPVYDYVPQI LRWITEWSEH FCELQEKNYY LLKEKCADYI QKDSKPIDDS HN IKCNTCK TKCEEYSKFI KKWNSQYINL EKKFKELYDE ANNTKSYEEL YRIGKPSHRN HYEDENLIQF LQNVKSECNE PNT VDKYLM YTSDCRRVKF SNTIDTNVNK PTADVTHNTI NGPSSNLPVV TETNIKNELR EYAFLETPEG YGNACKCKGP EPLD RCPEN DNISNYCNDF VSVPECTAKI YKDEIDHWNN ANVKFKTSIN NGVLVPPRRS HICLKNMITK NYDKKKNGME KFKTD LLQV AYNEGYFLCQ KYDKQPRDVL EAMKYTFADI ADIVKGRDMI NKDISAKLRK LLDIKVEPKA PRKWWKYNKA HVWHAM LCG YRKGGGTITN DECNVPDEEY TYQFLRWFQE WIKKFCTGQQ KLYDDVQTKC SSANCNRDDG TISLPECESS CVQYKNY IT RKRQEYRSLN HQYNMNFKEQ KAQGMKATQY IDDKCNSKCD CLIKYIDREK EWTNIYDSLE NNDLKNKCDC KQIKPKRH P KEVNPEEEPA NSEPDYIVPL VPQKPSTPEV PPPPPPPLPT PSDEPFHHHH HH

UniProtKB: Erythrocyte membrane protein 2 variant TM284var1

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Macromolecule #2: Immunoglobulin heavy constant mu

MacromoleculeName: Immunoglobulin heavy constant mu / type: protein_or_peptide / ID: 2 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.875766 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ASAWSHPQFE KGGGSGGGSG GSAWSHPQFE KIDTTIAELP PKVSVFVPPR DGFFGNPRKS KLICQATGFS PRQIQVSWLR EGKQVGSGV TTDQVQAEAK ESGPTTYKVT STLTIKESDW LGQSMFTCRV DHRGLTFQQN ASSMCVPDQD TAIRVFAIPP S FASIFLTK ...String:
ASAWSHPQFE KGGGSGGGSG GSAWSHPQFE KIDTTIAELP PKVSVFVPPR DGFFGNPRKS KLICQATGFS PRQIQVSWLR EGKQVGSGV TTDQVQAEAK ESGPTTYKVT STLTIKESDW LGQSMFTCRV DHRGLTFQQN ASSMCVPDQD TAIRVFAIPP S FASIFLTK STKLTCLVTD LTTYDSVTIS WTRQNGEAVK THTNISESHP NATFSAVGEA SICEDDWNSG ERFTCTVTHT DL PSPLKQT ISRPKGVALH RPDVYLLPPA REQLNLRESA TITCLVTGFS PADVFVQWMQ RGQPLSPEKY VTSAPMPEPQ APG RYFAHS ILTVSEEEWN TGETYTCVVA HEALPNRVTE RTVDKSTGKP TLYNVSLVMS DTAGTCY

UniProtKB: Immunoglobulin heavy constant mu

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Macromolecule #3: Immunoglobulin J chain

MacromoleculeName: Immunoglobulin J chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.483329 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
EDERIVLVDN KCKCARITSR IIRSSEDPNE DIVERNIRII VPLNNRENIS DPTSPLRTRF VYHLSDLCKK CDPTEVELDN QIVTATQSN ICDEDSATET CYTYDRNKCY TAVVPLVYGG ETKMVETALT PDACYPD

UniProtKB: Immunoglobulin J chain

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 10 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 59.74 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: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.62 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 849826
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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