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- PDB-7d3e: Cryo-EM structure of human DUOX1-DUOXA1 in low-calcium state -

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Basic information

Entry
Database: PDB / ID: 7d3e
TitleCryo-EM structure of human DUOX1-DUOXA1 in low-calcium state
Components
  • Dual oxidase 1
  • Isoform 2 of Dual oxidase maturation factor 1
KeywordsELECTRON TRANSPORT / DUOX / DUOXA / NOX / NADPH / FAD / Haem
Function / homology
Function and homology information


NADH oxidase H202-forming activity / regulation of thyroid hormone generation / NADPH oxidase H202-forming activity / cuticle development / NAD(P)H oxidase (H2O2-forming) / Thyroxine biosynthesis / positive regulation of hydrogen peroxide biosynthetic process / superoxide-generating NAD(P)H oxidase activity / hormone biosynthetic process / NAD(P)H oxidase H2O2-forming activity ...NADH oxidase H202-forming activity / regulation of thyroid hormone generation / NADPH oxidase H202-forming activity / cuticle development / NAD(P)H oxidase (H2O2-forming) / Thyroxine biosynthesis / positive regulation of hydrogen peroxide biosynthetic process / superoxide-generating NAD(P)H oxidase activity / hormone biosynthetic process / NAD(P)H oxidase H2O2-forming activity / NADPH oxidase complex / thyroid hormone generation / superoxide anion generation / hydrogen peroxide biosynthetic process / positive regulation of cell motility / hydrogen peroxide metabolic process / positive regulation of wound healing / cell leading edge / Oxidoreductases; Acting on a peroxide as acceptor; Peroxidases / response to cAMP / positive regulation of neuron differentiation / hydrogen peroxide catabolic process / peroxidase activity / defense response / cytokine-mediated signaling pathway / protein localization / protein transport / NADP binding / regulation of inflammatory response / response to oxidative stress / apical plasma membrane / calcium ion binding / heme binding / endoplasmic reticulum membrane / enzyme binding / cell surface / endoplasmic reticulum / membrane / plasma membrane
Similarity search - Function
Dual oxidase maturation factor / Dual oxidase, peroxidase domain / Dual oxidase maturation factor / Ferric reductase, NAD binding domain / : / Ferric reductase NAD binding domain / FAD-binding 8 / FAD-binding domain / Ferric reductase transmembrane component-like domain / Ferric reductase like transmembrane component ...Dual oxidase maturation factor / Dual oxidase, peroxidase domain / Dual oxidase maturation factor / Ferric reductase, NAD binding domain / : / Ferric reductase NAD binding domain / FAD-binding 8 / FAD-binding domain / Ferric reductase transmembrane component-like domain / Ferric reductase like transmembrane component / Haem peroxidase, animal-type / Haem peroxidase domain superfamily, animal type / Animal haem peroxidase / Animal heme peroxidase superfamily profile. / EF hand / Haem peroxidase superfamily / FAD-binding domain, ferredoxin reductase-type / Ferredoxin-NADP reductase (FNR), nucleotide-binding domain / Ferredoxin reductase-type FAD binding domain profile. / Riboflavin synthase-like beta-barrel / EF-hand domain pair / EF-hand, calcium binding motif / EF-Hand 1, calcium-binding site / EF-hand calcium-binding domain. / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair
Similarity search - Domain/homology
FLAVIN-ADENINE DINUCLEOTIDE / PROTOPORPHYRIN IX CONTAINING FE / Chem-NDP / Dual oxidase maturation factor 1 / Dual oxidase 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsChen, L. / Wu, J.X.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)91957201 China
National Natural Science Foundation of China (NSFC)31622021 China
CitationJournal: Nat Commun / Year: 2021
Title: Structures of human dual oxidase 1 complex in low-calcium and high-calcium states.
Authors: Jing-Xiang Wu / Rui Liu / Kangcheng Song / Lei Chen /
Abstract: Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. They are involved in many crucial biological processes and human diseases, ...Dual oxidases (DUOXs) produce hydrogen peroxide by transferring electrons from intracellular NADPH to extracellular oxygen. They are involved in many crucial biological processes and human diseases, especially in thyroid diseases. DUOXs are protein complexes co-assembled from the catalytic DUOX subunits and the auxiliary DUOXA subunits and their activities are regulated by intracellular calcium concentrations. Here, we report the cryo-EM structures of human DUOX1-DUOXA1 complex in both high-calcium and low-calcium states. These structures reveal the DUOX1 complex is a symmetric 2:2 hetero-tetramer stabilized by extensive inter-subunit interactions. Substrate NADPH and cofactor FAD are sandwiched between transmembrane domain and the cytosolic dehydrogenase domain of DUOX. In the presence of calcium ions, intracellular EF-hand modules might enhance the catalytic activity of DUOX by stabilizing the dehydrogenase domain in a conformation that allows electron transfer.
History
DepositionSep 19, 2020Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 9, 2020Provider: repository / Type: Initial release
Revision 1.1Jun 23, 2021Group: Database references / Category: 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.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Nov 6, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Dual oxidase 1
B: Isoform 2 of Dual oxidase maturation factor 1
C: Dual oxidase 1
D: Isoform 2 of Dual oxidase maturation factor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)473,40128
Polymers462,1264
Non-polymers11,27524
Water362
1


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

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Components

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Protein , 2 types, 4 molecules ACBD

#1: Protein Dual oxidase 1 / Large NOX 1 / Long NOX 1 / NADPH thyroid oxidase 1 / Thyroid oxidase 1


Mass: 177483.828 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DUOX1, DUOX, LNOX1, THOX1 / Production host: Homo sapiens (human)
References: UniProt: Q9NRD9, Oxidoreductases; Acting on a peroxide as acceptor; Peroxidases, NAD(P)H oxidase (H2O2-forming)
#2: Protein Isoform 2 of Dual oxidase maturation factor 1 / Dual oxidase activator 1 / Numb-interacting protein


Mass: 53579.188 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DUOXA1, NIP, NUMBIP / Production host: Homo sapiens (human) / References: UniProt: Q1HG43

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Sugars , 2 types, 12 molecules

#3: Polysaccharide alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D- ...alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1721.527 Da / Num. of mol.: 2 / Source method: obtained synthetically
DescriptorTypeProgram
DManpa1-2DManpa1-2DManpa1-3[DManpa1-2DManpa1-6[DManpa1-3]DManpa1-6]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,10,9/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3-3-3-3-3/a4-b1_b4-c1_c3-d1_c6-g1_d2-e1_e2-f1_g3-h1_g6-i1_i2-j1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{[(2+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}}[(6+1)][a-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{[(2+1)][a-D-Manp]{}}}}}}LINUCSPDB-CARE
#7: 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.: 10 / Source method: isolated from a natural source / 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

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Non-polymers , 5 types, 14 molecules

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


Mass: 616.487 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H32FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-NDP / NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE


Mass: 745.421 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H30N7O17P3 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-FAD / FLAVIN-ADENINE DINUCLEOTIDE


Mass: 785.550 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C27H33N9O15P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: FAD*YM
#8: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: Na
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: H2O

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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: human DUOX1-DUOXA1 complex / Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7
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 FIELD
Image recordingElectron dose: 48 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 125984 / Symmetry type: POINT

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