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- PDB-9fmu: Cryo-EM structure of human CD163 SRCR1-9 in complex with haptoglo... -

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Basic information

Entry
Database: PDB / ID: 9fmu
TitleCryo-EM structure of human CD163 SRCR1-9 in complex with haptoglobin-hemoglobin
Components
  • Hemopressin
  • Isoform 2 of Haptoglobin
  • Scavenger receptor cysteine-rich type 1 protein M130
  • Spinorphin
KeywordsENDOCYTOSIS / Scavenging receptor / oxygen transport / complex / hemolysis / inflammation
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
PROTOPORPHYRIN IX CONTAINING FE / Haptoglobin / Hemoglobin subunit beta / Hemoglobin subunit alpha / Scavenger receptor cysteine-rich type 1 protein M130
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.46 Å
AuthorsAndersen, C.B.F. / Kollman, J.M.
Funding support Denmark, 1items
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
DepositionJun 7, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 18, 2024Provider: repository / Type: Initial release
Revision 1.1Jan 22, 2025Group: Data collection / Database references / Category: citation / citation_author / em_admin
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.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _em_admin.last_update
Revision 1.2Feb 12, 2025Group: Data collection / Category: em_admin / Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Hemopressin
B: Spinorphin
C: Isoform 2 of Haptoglobin
D: Scavenger receptor cysteine-rich type 1 protein M130
E: Scavenger receptor cysteine-rich type 1 protein M130
hetero molecules


Theoretical massNumber of molelcules
Total (without water)296,86015
Polymers294,4005
Non-polymers2,45910
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

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Protein , 4 types, 5 molecules ABCDE

#1: Protein Hemopressin


Mass: 15281.550 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P69905
#2: Protein Spinorphin


Mass: 16021.396 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P68871
#3: Protein Isoform 2 of Haptoglobin / Zonulin


Mass: 38497.652 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00738
#4: Protein Scavenger receptor cysteine-rich type 1 protein M130 / Hemoglobin scavenger receptor


Mass: 112299.836 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD163, M130 / Production host: Cricetulus griseus (Chinese hamster) / References: UniProt: Q86VB7

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Sugars , 1 types, 5 molecules

#6: 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.: 5 / 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

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Non-polymers , 2 types, 5 molecules

#5: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION

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Details

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: CD163 in complex with haptoglobin-hemoglobin / Type: COMPLEX / Entity ID: #1-#4 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.6
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: C-flat
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 FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 90 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.4particle selection
4cryoSPARC4.4CTF correction
10cryoSPARC4.4initial Euler assignment
11cryoSPARC4.4final Euler assignment
12cryoSPARCclassification
13cryoSPARC4.43D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 357824
3D reconstructionResolution: 4.46 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 38511 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00515309
ELECTRON MICROSCOPYf_angle_d1.17720793
ELECTRON MICROSCOPYf_dihedral_angle_d7.2092175
ELECTRON MICROSCOPYf_chiral_restr0.0652231
ELECTRON MICROSCOPYf_plane_restr0.0092695

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