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- EMDB-50444: Cryo-EM structure of human CD163 SRCR2-4 in complex with haptoglo... -

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Basic information

Entry
Database: EMDB / ID: EMD-50444
TitleCryo-EM structure of human CD163 SRCR2-4 in complex with haptoglobin-hemoglobin
Map dataMap from focused refinement using a mask covering haptoglobin-hemoglobin and CD163 SRCR 2-4
Sample
  • Complex: CD163 in complex with haptoglobin-hemoglobin
    • Complex: CD163
      • Protein or peptide: Scavenger receptor cysteine-rich type 1 protein M130
    • Complex: haptoglobin-hemoglobin complex
      • Protein or peptide: Hemoglobin subunit alpha
      • Protein or peptide: Hemoglobin subunit beta
      • Protein or peptide: Haptoglobin
  • Ligand: PROTOPORPHYRIN IX CONTAINING FE
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION
KeywordsScavenging receptor / oxygen transport / complex / hemolysis / inflammation / ENDOCYTOSIS
Function / homology
Function and homology information


negative regulation of hydrogen peroxide catabolic process / negative regulation of oxidoreductase activity / zymogen activation / CD163 mediating an anti-inflammatory response / scavenger receptor activity / nitric oxide transport / hemoglobin alpha binding / cellular oxidant detoxification / hemoglobin binding / renal absorption ...negative regulation of hydrogen peroxide catabolic process / negative regulation of oxidoreductase activity / zymogen activation / CD163 mediating an anti-inflammatory response / scavenger receptor activity / nitric oxide transport / hemoglobin alpha binding / cellular oxidant detoxification / hemoglobin binding / renal absorption / haptoglobin-hemoglobin complex / hemoglobin complex / antioxidant activity / oxygen transport / immune system process / Scavenging of heme from plasma / endocytic vesicle lumen / blood vessel diameter maintenance / acute-phase response / hydrogen peroxide catabolic process / oxygen carrier activity / carbon dioxide transport / Heme signaling / Erythrocytes take up oxygen and release carbon dioxide / Erythrocytes take up carbon dioxide and release oxygen / defense response / Late endosomal microautophagy / Cytoprotection by HMOX1 / response to hydrogen peroxide / oxygen binding / regulation of blood pressure / platelet aggregation / specific granule lumen / Chaperone Mediated Autophagy / positive regulation of nitric oxide biosynthetic process / endocytic vesicle membrane / tertiary granule lumen / Factors involved in megakaryocyte development and platelet production / scaffold protein binding / blood microparticle / ficolin-1-rich granule lumen / defense response to bacterium / iron ion binding / external side of plasma membrane / serine-type endopeptidase activity / heme binding / Neutrophil degranulation / extracellular space / extracellular exosome / extracellular region / metal ion binding / membrane / plasma membrane / cytosol
Similarity search - Function
SRCR domain signature. / Scavenger receptor cysteine-rich domain / SRCR domain profile. / SRCR-like domain superfamily / Scavenger receptor Cys-rich / SRCR domain / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / Hemoglobin, pi ...SRCR domain signature. / Scavenger receptor cysteine-rich domain / SRCR domain profile. / SRCR-like domain superfamily / Scavenger receptor Cys-rich / SRCR domain / Sushi/SCR/CCP domain / Sushi/CCP/SCR domain profile. / Sushi/SCR/CCP superfamily / Hemoglobin, pi / Hemoglobin, alpha-type / Hemoglobin, beta-type / : / Globin/Protoglobin / Globin domain profile. / Globin / Globin / Globin-like superfamily / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Haptoglobin / Hemoglobin subunit beta / Hemoglobin subunit alpha / Scavenger receptor cysteine-rich type 1 protein M130
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.87 Å
AuthorsAndersen CBF / Kollman JM
Funding support Denmark, 1 items
OrganizationGrant numberCountry
LundbeckfondenR291-2018-49 Denmark
CitationJournal: Nat Commun / Year: 2024
Title: The Cryo-EM structure of human CD163 bound to haptoglobin-hemoglobin reveals molecular mechanisms of hemoglobin scavenging.
Authors: Anders Etzerodt / Jakob Hauge Mikkelsen / Morten Torvund-Jensen / Dorle Hennig / Thomas Boesen / Jonas Heilskov Graversen / Søren Kragh Moestrup / Justin M Kollman / Christian Brix Folsted Andersen /
Abstract: CD163, a macrophage-specific receptor, plays a critical role in scavenging hemoglobin released during hemolysis, protecting against oxidative effects of heme iron. In the bloodstream, hemoglobin is ...CD163, a macrophage-specific receptor, plays a critical role in scavenging hemoglobin released during hemolysis, protecting against oxidative effects of heme iron. In the bloodstream, hemoglobin is bound by haptoglobin, leading to its immediate endocytosis by CD163. While haptoglobin's structure and function are well understood, CD163's structure and its interaction with the haptoglobin-hemoglobin complex have remained elusive. Here, we present the cryo-electron microscopy structure of the entire extracellular domain of human CD163 in complex with haptoglobin-hemoglobin. The structure reveals that CD163 assembles into trimers (and to some extent dimers), binding haptoglobin-hemoglobin in their center. Key acidic residues in CD163 interact with lysine residues from both haptoglobin and hemoglobin. Calcium-binding sites located near the haptoglobin-hemoglobin interface in CD163 provide explanation for the calcium dependence of the interaction. Furthermore, we show that the interaction facilitating CD163 oligomerization mimics ligand binding and is also calcium dependent. This structural insight into CD163 advances our understanding of its role in hemoglobin scavenging as well as its broader relevance to structurally related scavenger receptors.
History
DepositionMay 27, 2024-
Header (metadata) releaseDec 18, 2024-
Map releaseDec 18, 2024-
UpdateFeb 12, 2025-
Current statusFeb 12, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50444.png

Downloads & links

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Map

FileDownload / File: emd_50444.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMap from focused refinement using a mask covering haptoglobin-hemoglobin and CD163 SRCR 2-4
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 320 pix.
= 339.2 Å		1.06 Å/pix.
x 320 pix.
= 339.2 Å		1.06 Å/pix.
x 320 pix.
= 339.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.0
Minimum - Maximum-3.6951184 - 6.050188
Average (Standard dev.)0.050303545 (±0.13080889)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 339.19998 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_50444_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map from focused refinement using a mask...

Fileemd_50444_half_map_1.map
AnnotationHalf map from focused refinement using a mask covering haptoglobin-hemoglobin and CD163 SRCR 2-4
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map from focused refinement using a mask...

Fileemd_50444_half_map_2.map
AnnotationHalf map from focused refinement using a mask covering haptoglobin-hemoglobin and CD163 SRCR 2-4
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : CD163 in complex with haptoglobin-hemoglobin

EntireName: CD163 in complex with haptoglobin-hemoglobin
Components
  • Complex: CD163 in complex with haptoglobin-hemoglobin
    • Complex: CD163
      • Protein or peptide: Scavenger receptor cysteine-rich type 1 protein M130
    • Complex: haptoglobin-hemoglobin complex
      • Protein or peptide: Hemoglobin subunit alpha
      • Protein or peptide: Hemoglobin subunit beta
      • Protein or peptide: Haptoglobin
  • Ligand: PROTOPORPHYRIN IX CONTAINING FE
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: CALCIUM ION

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Supramolecule #1: CD163 in complex with haptoglobin-hemoglobin

SupramoleculeName: CD163 in complex with haptoglobin-hemoglobin / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4

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Supramolecule #2: CD163

SupramoleculeName: CD163 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #4
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: haptoglobin-hemoglobin complex

SupramoleculeName: haptoglobin-hemoglobin complex / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Hemoglobin subunit alpha

MacromoleculeName: Hemoglobin subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.28155 KDa
SequenceString:
MVLSPADKTN VKAAWGKVGA HAGEYGAEAL ERMFLSFPTT KTYFPHFDLS HGSAQVKGHG KKVADALTNA VAHVDDMPNA LSALSDLHA HKLRVDPVNF KLLSHCLLVT LAAHLPAEFT PAVHASLDKF LASVSTVLTS KYR

UniProtKB: Hemoglobin subunit alpha

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Macromolecule #2: Hemoglobin subunit beta

MacromoleculeName: Hemoglobin subunit beta / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 16.021396 KDa
SequenceString:
MVHLTPEEKS AVTALWGKVN VDEVGGEALG RLLVVYPWTQ RFFESFGDLS TPDAVMGNPK VKAHGKKVLG AFSDGLAHLD NLKGTFATL SELHCDKLHV DPENFRLLGN VLVCVLAHHF GKEFTPPVQA AYQKVVAGVA NALAHKYH

UniProtKB: Hemoglobin subunit beta

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Macromolecule #3: Haptoglobin

MacromoleculeName: Haptoglobin / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.262184 KDa
SequenceString: MSALGAVIAL LLWGQLFAVD SGNDVTDIAD DGCPKPPEIA HGYVEHSVRY QCKNYYKLRT EGDGVYTLND KKQWINKAVG DKLPECEAD DGCPKPPEIA HGYVEHSVRY QCKNYYKLRT EGDGVYTLNN EKQWINKAVG DKLPECEAVC GKPKNPANPV Q RILGGHLD ...String:
MSALGAVIAL LLWGQLFAVD SGNDVTDIAD DGCPKPPEIA HGYVEHSVRY QCKNYYKLRT EGDGVYTLND KKQWINKAVG DKLPECEAD DGCPKPPEIA HGYVEHSVRY QCKNYYKLRT EGDGVYTLNN EKQWINKAVG DKLPECEAVC GKPKNPANPV Q RILGGHLD AKGSFPWQAK MVSHHNLTTG ATLINEQWLL TTAKNLFLNH SENATAKDIA PTLTLYVGKK QLVEIEKVVL HP NYSQVDI GLIKLKQKVS VNERVMPICL PSKDYAEVGR VGYVSGWGRN ANFKFTDHLK YVMLPVADQD QCIRHYEGST VPE KKTPKS PVGVQPILNE HTFCAGMSKY QEDTCYGDAG SAFAVHDLEE DTWYATGILS FDKSCAVAEY GVYVKVTSIQ DWVQ KTIAE N

UniProtKB: Haptoglobin

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Macromolecule #4: Scavenger receptor cysteine-rich type 1 protein M130

MacromoleculeName: Scavenger receptor cysteine-rich type 1 protein M130 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 125.594805 KDa
Recombinant expressionOrganism: Cricetulus griseus (Chinese hamster)
SequenceString: MSKLRMVLLE DSGSADFRRH FVNLSPFTIT VVLLLSACFV TSSLGGTDKE LRLVDGENKC SGRVEVKVQE EWGTVCNNGW SMEAVSVIC NQLGCPTAIK APGWANSSAG SGRIWMDHVS CRGNESALWD CKHDGWGKHS NCTHQQDAGV TCSDGSNLEM R LTRGGNMC ...String:
MSKLRMVLLE DSGSADFRRH FVNLSPFTIT VVLLLSACFV TSSLGGTDKE LRLVDGENKC SGRVEVKVQE EWGTVCNNGW SMEAVSVIC NQLGCPTAIK APGWANSSAG SGRIWMDHVS CRGNESALWD CKHDGWGKHS NCTHQQDAGV TCSDGSNLEM R LTRGGNMC SGRIEIKFQG RWGTVCDDNF NIDHASVICR QLECGSAVSF SGSSNFGEGS GPIWFDDLIC NGNESALWNC KH QGWGKHN CDHAEDAGVI CSKGADLSLR LVDGVTECSG RLEVRFQGEW GTICDDGWDS YDAAVACKQL GCPTAVTAIG RVN ASKGFG HIWLDSVSCQ GHEPAIWQCK HHEWGKHYCN HNEDAGVTCS DGSDLELRLR GGGSRCAGTV EVEIQRLLGK VCDR GWGLK EADVVCRQLG CGSALKTSYQ VYSKIQATNT WLFLSSCNGN ETSLWDCKNW QWGGLTCDHY EEAKITCSAH REPRL VGGD IPCSGRVEVK HGDTWGSICD SDFSLEAASV LCRELQCGTV VSILGGAHFG EGNGQIWAEE FQCEGHESHL SLCPVA PRP EGTCSHSRDV GVVCSRYTEI RLVNGKTPCE GRVELKTLGA WGSLCNSHWD IEDAHVLCQQ LKCGVALSTP GGARFGK GN GQIWRHMFHC TGTEQHMGDC PVTALGASLC PSEQVASVIC SGNQSQTLSS CNSSSLGPTR PTIPEESAVA CIESGQLR L VNGGGRCAGR VEIYHEGSWG TICDDSWDLS DAHVVCRQLG CGEAINATGS AHFGEGTGPI WLDEMKCNGK ESRIWQCHS HGWGQQNCRH KEDAGVICSE FMSLRLTSEA SREACAGRLE VFYNGAWGTV GKSSMSETTV GVVCRQLGCA DKGKINPASL DKAMSIPMW VDNVQCPKGP DTLWQCPSSP WEKRLASPSE ETWITCDNKI RLQEGPTSCS GRVEIWHGGS WGTVCDDSWD L DDAQVVCQ QLGCGPALKA FKEAEFGQGT GPIWLNEVKC KGNESSLWDC PARRWGHSEC GHKEDAAVNC TDISVQKTPQ KA TTGRSSR QSSFIAVGIL GVVLLAIFVA LFFLTKKRRQ RQRLAVSSRG ENLVHQIQYR EMNSCLNADD LDLMNSSENS HES ADFSAA ELISVSKFLP ISGMEKEAIL SHTEKENGNL

UniProtKB: Scavenger receptor cysteine-rich type 1 protein M130

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Macromolecule #5: PROTOPORPHYRIN IX CONTAINING FE

MacromoleculeName: PROTOPORPHYRIN IX CONTAINING FE / type: ligand / ID: 5 / Number of copies: 2 / Formula: HEM
Molecular weightTheoretical: 616.487 Da
Chemical component information

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE

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Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 3 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

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

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Macromolecule #7: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 7 / Number of copies: 2 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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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: 7.6
GridModel: C-flat / Material: COPPER / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 45 sec.
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 90.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 357824
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

4wjg

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.87 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4) / Number images used: 57262
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.4)
Final 3D classificationSoftware - Name: cryoSPARC (ver. 4.4)
FSC plot (resolution estimation)

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