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- EMDB-21149: Cryo-EM structure of IRP2-FBXL5-SKP1 complex -

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Basic information

Entry
Database: EMDB / ID: EMD-21149
TitleCryo-EM structure of IRP2-FBXL5-SKP1 complex
Map dataIRP2-FBXL5-SKP1 complex
Sample
  • Complex: IRP2-FBLX5-SKP1 complex
    • Protein or peptide: Iron-responsive element binding protein 2, isoform CRA_a
    • Protein or peptide: F-box/LRR-repeat protein 5
    • Protein or peptide: S-phase kinase-associated protein 1
  • Ligand: FE2/S2 (INORGANIC) CLUSTER
KeywordsE3 ligase / [2Fe-2S] cluster / Iron metabolism / LIGASE
Function / homology
Function and homology information


aconitate hydratase activity / iron-responsive element binding / : / F-box domain binding / citrate metabolic process / PcG protein complex / protoporphyrinogen IX biosynthetic process / Cul7-RING ubiquitin ligase complex / positive regulation of ubiquitin protein ligase activity / maintenance of protein location in nucleus ...aconitate hydratase activity / iron-responsive element binding / : / F-box domain binding / citrate metabolic process / PcG protein complex / protoporphyrinogen IX biosynthetic process / Cul7-RING ubiquitin ligase complex / positive regulation of ubiquitin protein ligase activity / maintenance of protein location in nucleus / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / erythrocyte homeostasis / intestinal absorption / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / SCF ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / Prolactin receptor signaling / protein monoubiquitination / Association of TriC/CCT with target proteins during biosynthesis / cullin family protein binding / ubiquitin-like ligase-substrate adaptor activity / protein K48-linked ubiquitination / Nuclear events stimulated by ALK signaling in cancer / ubiquitin ligase complex / translation repressor activity / tricarboxylic acid cycle / Regulation of BACH1 activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / post-embryonic development / osteoclast differentiation / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / molecular function activator activity / Vpu mediated degradation of CD4 / Dectin-1 mediated noncanonical NF-kB signaling / Degradation of GLI1 by the proteasome / Activation of NF-kappaB in B cells / Negative regulation of NOTCH4 signaling / Iron uptake and transport / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / Degradation of beta-catenin by the destruction complex / 2 iron, 2 sulfur cluster binding / NOTCH1 Intracellular Domain Regulates Transcription / CLEC7A (Dectin-1) signaling / beta-catenin binding / SCF(Skp2)-mediated degradation of p27/p21 / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / multicellular organismal-level iron ion homeostasis / FCERI mediated NF-kB activation / Interleukin-1 signaling / protein polyubiquitination / Orc1 removal from chromatin / ubiquitin-protein transferase activity / positive regulation of protein catabolic process / Regulation of RUNX2 expression and activity / Cyclin D associated events in G1 / Regulation of PLK1 Activity at G2/M Transition / Antigen processing: Ubiquitination & Proteasome degradation / Circadian Clock / Downstream TCR signaling / Neddylation / 4 iron, 4 sulfur cluster binding / iron ion transport / proteasome-mediated ubiquitin-dependent protein catabolic process / intracellular iron ion homeostasis / protein ubiquitination / chromatin remodeling / iron ion binding / protein domain specific binding / centrosome / perinuclear region of cytoplasm / mitochondrion / RNA binding / nucleoplasm / metal ion binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Iron regulatory protein 2 / Aconitase/Iron-responsive element-binding protein 2 / Aconitase A, swivel domain / FBXL5-like, hemerythrin-like domain / Aconitase/3-isopropylmalate dehydratase large subunit, alpha/beta/alpha domain / Aconitase/3-isopropylmalate dehydratase large subunit, alpha/beta/alpha, subdomain 1/3 / Aconitase family, 4Fe-4S cluster binding site / Aconitase, iron-sulfur domain / Aconitase family (aconitate hydratase) / Aconitase family signature 1. ...Iron regulatory protein 2 / Aconitase/Iron-responsive element-binding protein 2 / Aconitase A, swivel domain / FBXL5-like, hemerythrin-like domain / Aconitase/3-isopropylmalate dehydratase large subunit, alpha/beta/alpha domain / Aconitase/3-isopropylmalate dehydratase large subunit, alpha/beta/alpha, subdomain 1/3 / Aconitase family, 4Fe-4S cluster binding site / Aconitase, iron-sulfur domain / Aconitase family (aconitate hydratase) / Aconitase family signature 1. / Aconitase family signature 2. / Aconitase A/isopropylmalate dehydratase small subunit, swivel domain / Aconitase C-terminal domain / Aconitase/3-isopropylmalate dehydratase, swivel / Hemerythrin-like / Hemerythrin HHE cation binding domain / Leucine-rich repeat, cysteine-containing subtype / Leucine-rich repeat - CC (cysteine-containing) subfamily / A Receptor for Ubiquitination Targets / F-box domain profile. / F-box-like domain superfamily / F-box-like / SKP1 component, dimerisation / S-phase kinase-associated protein 1 / SKP1-like, dimerisation domain superfamily / Skp1 family, dimerisation domain / F-box domain / Leucine Rich repeat / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / SKP1/BTB/POZ domain superfamily / Leucine-rich repeat / Leucine-rich repeat domain superfamily
Similarity search - Domain/homology
Iron-responsive element-binding protein 2 / Iron-responsive element-binding protein 2 / S-phase kinase-associated protein 1 / F-box/LRR-repeat protein 5
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsWang H / Shi H
Funding support United States, 1 items
OrganizationGrant numberCountry
Howard Hughes Medical Institute United States
CitationJournal: Mol Cell / Year: 2020
Title: FBXL5 Regulates IRP2 Stability in Iron Homeostasis via an Oxygen-Responsive [2Fe2S] Cluster.
Authors: Hui Wang / Hui Shi / Malini Rajan / Elizabeth R Canarie / Seoyeon Hong / Daniele Simoneschi / Michele Pagano / Matthew F Bush / Stefan Stoll / Elizabeth A Leibold / Ning Zheng /
Abstract: Cellular iron homeostasis is dominated by FBXL5-mediated degradation of iron regulatory protein 2 (IRP2), which is dependent on both iron and oxygen. However, how the physical interaction between ...Cellular iron homeostasis is dominated by FBXL5-mediated degradation of iron regulatory protein 2 (IRP2), which is dependent on both iron and oxygen. However, how the physical interaction between FBXL5 and IRP2 is regulated remains elusive. Here, we show that the C-terminal substrate-binding domain of FBXL5 harbors a [2Fe2S] cluster in the oxidized state. A cryoelectron microscopy (cryo-EM) structure of the IRP2-FBXL5-SKP1 complex reveals that the cluster organizes the FBXL5 C-terminal loop responsible for recruiting IRP2. Interestingly, IRP2 binding to FBXL5 hinges on the oxidized state of the [2Fe2S] cluster maintained by ambient oxygen, which could explain hypoxia-induced IRP2 stabilization. Steric incompatibility also allows FBXL5 to physically dislodge IRP2 from iron-responsive element RNA to facilitate its turnover. Taken together, our studies have identified an iron-sulfur cluster within FBXL5, which promotes IRP2 polyubiquitination and degradation in response to both iron and oxygen concentrations.
History
DepositionDec 20, 2019-
Header (metadata) releaseJan 29, 2020-
Map releaseAug 5, 2020-
UpdateMar 6, 2024-
Current statusMar 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.03
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  • Surface view colored by radius
  • Surface level: 0.03
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  • Surface view with fitted model
  • Atomic models: PDB-6vcd
  • Surface level: 0.03
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_21149.png

Downloads & links

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Map

FileDownload / File: emd_21149.map.gz / Format: CCP4 / Size: 129.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationIRP2-FBXL5-SKP1 complex
Voxel sizeX=Y=Z: 1.056 Å
Density
Contour LevelBy AUTHOR: 0.03 / Movie #1: 0.03
Minimum - Maximum-0.16048244 - 0.27316839
Average (Standard dev.)0.00006698928 (±0.0030271355)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions324324324
Spacing324324324
CellA=B=C: 342.144 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0561.0561.056
M x/y/z324324324
origin x/y/z0.0000.0000.000
length x/y/z342.144342.144342.144
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS324324324
D min/max/mean-0.1600.2730.000

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Supplemental data

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Sample components

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Entire : IRP2-FBLX5-SKP1 complex

EntireName: IRP2-FBLX5-SKP1 complex
Components
  • Complex: IRP2-FBLX5-SKP1 complex
    • Protein or peptide: Iron-responsive element binding protein 2, isoform CRA_a
    • Protein or peptide: F-box/LRR-repeat protein 5
    • Protein or peptide: S-phase kinase-associated protein 1
  • Ligand: FE2/S2 (INORGANIC) CLUSTER

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Supramolecule #1: IRP2-FBLX5-SKP1 complex

SupramoleculeName: IRP2-FBLX5-SKP1 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Iron-responsive element binding protein 2, isoform CRA_a

MacromoleculeName: Iron-responsive element binding protein 2, isoform CRA_a
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 105.165328 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MDAPKAGYAF EYLIETLNDS SHKKFFDVSK LGTKYDVLPY SIRVLLEAAV RNCDGFLMKK EDVMNILDWK TKQSNVEVPF FPARVLLQD FTGIPAMVDF AAMREAVKTL GGDPEKVHPA CPTDLTVDHS LQIDFSKCAI QNAPNPGGGD LQKAGKLSPL K VQPKKLPC ...String:
MDAPKAGYAF EYLIETLNDS SHKKFFDVSK LGTKYDVLPY SIRVLLEAAV RNCDGFLMKK EDVMNILDWK TKQSNVEVPF FPARVLLQD FTGIPAMVDF AAMREAVKTL GGDPEKVHPA CPTDLTVDHS LQIDFSKCAI QNAPNPGGGD LQKAGKLSPL K VQPKKLPC RGQTTCRGSC DSGELGRNSG TFSSQIENTP ILCPFHLQPV PEPETVLKNQ EVEFGRNRER LQFFKWSSRV FK NVAVIPP GTGMAHQINL EYLSRVVFEE KDLLFPDSVV GTDSHITMVN GLGILGWGVG GIETEAVMLG LPVSLTLPEV VGC ELTGSS NPFVTSIDVV LGITKHLRQV GVAGKFVEFF GSGVSQLSIV DRTTIANMCP EYGAILSFFP VDNVTLKHLE HTGF SKAKL ESMETYLKAV KLFRNDQNSS GEPEYSQVIQ INLNSIVPSV SGPKRPQDRV AVTDMKSDFQ ACLNEKVGFK GFQIA AEKQ KDIVSIHYEG SEYKLSHGSV VIAAVISCTN NCNPSVMLAA GLLAKKAVEA GLRVKPYIRT SLSPGSGMVT HYLSSS GVL PYLSKLGFEI VGYGCSTCVG NTAPLSDAVL NAVKQGDLVT CGILSGNKNF EGRLCDCVRA NYLASPPLVV AYAIAGT VN IDFQTEPLGT DPTGKNIYLH DIWPSREEVH RVEEEHVILS MFKALKDKIE MGNKRWNSLE APDSVLFPWD LKSTYIRC P SFFDKLTKEP IALQAIENAH VLLYLGDSVT TDHISPAGSI ARNSAAAKYL TNRGLTPREF NSYGARRGND AVMTRGTFA NIKLFNKFIG KPAPKTIHFP SGQTLDVFEA AELYQKEGIP LIILAGKKYG SGNSRDWAAK GPYLLGVKAV LAESYEKIHK DHLIGIGIA PLQFLPGENA DSLGLSGRET FSLTFPEELS PGITLNIQTS TGKVFSVIAS FEDDVEITLY KHGGLLNFVA R KFS

UniProtKB: Iron-responsive element-binding protein 2

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Macromolecule #2: F-box/LRR-repeat protein 5

MacromoleculeName: F-box/LRR-repeat protein 5 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 54.832441 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: EHSTGITHLP PEVMLSIFSY LNPQELCRCS QVSMKWSQLT KTGSLWKHLY PVHWARGDWY SGPATELDTE PDDEWVKNRK DESRAFHEW DEDADIDESE ESAEESIAIS IAQMEKRLLH GLIHNVLPYV GTSVKTLVLA YSSAVSSKMV RQILELCPNL E HLDLTQTD ...String:
EHSTGITHLP PEVMLSIFSY LNPQELCRCS QVSMKWSQLT KTGSLWKHLY PVHWARGDWY SGPATELDTE PDDEWVKNRK DESRAFHEW DEDADIDESE ESAEESIAIS IAQMEKRLLH GLIHNVLPYV GTSVKTLVLA YSSAVSSKMV RQILELCPNL E HLDLTQTD ISDSAFDSWS WLGCCQSLRH LDLSGCEKIT DVALEKISRA LGILTSHQSG FLKTSTSKIT STAWKNKDIT MQ STKQYAC LHDLTNKGIG EEIDNEHPWT KPVSSENFTS PYVWMLDAED LADIEDTVEW RHRNVESLCV METASNFSCS TSG CFSKDI VGLRTSVCWQ QHCASPAFAY CGHSFCCTGT ALRTMSSLPE SSAMCRKAAR TRLPRGKDLI YFGSEKSDQE TGRV LLFLS LSGCYQITDH GLRVLTLGGG LPYLEHLNLS GCLTITGAGL QDLVSACPSL NDEYFYYCDN INGPHADTAS GCQNL QCGF RACCRSGE

UniProtKB: F-box/LRR-repeat protein 5

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Macromolecule #3: S-phase kinase-associated protein 1

MacromoleculeName: S-phase kinase-associated protein 1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.679965 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MPSIKLQSSD GEIFEVDVEI AKQSVTIKTM LEDLGMDDEG DDDPVPLPNV NAAILKKVIQ WCTHHKDDPP PPEDDENKEK RTDDIPVWD QEFLKVDQGT LFELILAANY LDIKGLLDVT CKTVANMIKG KTPEEIRKTF NIKNDFTEEE EAQVRKENQW C EEK

UniProtKB: S-phase kinase-associated protein 1

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Macromolecule #4: FE2/S2 (INORGANIC) CLUSTER

MacromoleculeName: FE2/S2 (INORGANIC) CLUSTER / type: ligand / ID: 4 / Number of copies: 1 / Formula: FES
Molecular weightTheoretical: 175.82 Da
Chemical component information

ChemComp-FES:
FE2/S2 (INORGANIC) CLUSTER / Iron–sulfur cluster

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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: 8
GridDetails: unspecified
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 73.8 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL / In silico model: generated by relion
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 955060

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