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- EMDB-28693: Cryo-EM structure of two IGF1 bound full-length mouse IGF1R mutan... -

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Basic information

Entry
Database: EMDB / ID: EMD-28693
TitleCryo-EM structure of two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation
Map dataCryo-EM structure of two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation
Sample
  • Complex: Two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation
    • Protein or peptide: Insulin-like growth factor 1 receptor
    • Protein or peptide: Insulin-like growth factor IInsulin-like growth factor 1
Function / homology
Function and homology information


Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / mitotic nuclear division / IRS-related events triggered by IGF1R / SHC-related events triggered by IGF1R / glycolate metabolic process / muscle hypertrophy / negative regulation of oocyte development / positive regulation of trophectodermal cell proliferation / insulin-like growth factor binding protein complex / insulin-like growth factor ternary complex ...Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / mitotic nuclear division / IRS-related events triggered by IGF1R / SHC-related events triggered by IGF1R / glycolate metabolic process / muscle hypertrophy / negative regulation of oocyte development / positive regulation of trophectodermal cell proliferation / insulin-like growth factor binding protein complex / insulin-like growth factor ternary complex / : / proteoglycan biosynthetic process / negative regulation of cholangiocyte apoptotic process / positive regulation of glycoprotein biosynthetic process / myotube cell development / Extra-nuclear estrogen signaling / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / negative regulation of neuroinflammatory response / insulin-like growth factor receptor activity / positive regulation of steroid hormone biosynthetic process / protein kinase complex / negative regulation of vascular associated smooth muscle cell apoptotic process / bone mineralization involved in bone maturation / protein transporter activity / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / positive regulation of cell growth involved in cardiac muscle cell development / IRS-related events triggered by IGF1R / insulin-like growth factor binding / exocytic vesicle / negative regulation of muscle cell apoptotic process / positive regulation of meiotic cell cycle / positive regulation of DNA metabolic process / positive regulation of developmental growth / cell activation / positive regulation of calcineurin-NFAT signaling cascade / male sex determination / prostate gland epithelium morphogenesis / exocrine pancreas development / mammary gland development / insulin receptor complex / negative regulation of hepatocyte apoptotic process / positive regulation of transcription regulatory region DNA binding / insulin-like growth factor I binding / insulin receptor activity / transcytosis / alphav-beta3 integrin-IGF-1-IGF1R complex / phosphatidylinositol-mediated signaling / positive regulation of kinase activity / positive regulation of Ras protein signal transduction / positive regulation of protein-containing complex disassembly / myoblast differentiation / positive regulation of insulin-like growth factor receptor signaling pathway / myoblast proliferation / cellular response to insulin-like growth factor stimulus / muscle organ development / negative regulation of interleukin-1 beta production / dendritic spine maintenance / response to L-glutamate / insulin binding / adrenal gland development / establishment of cell polarity / postsynaptic modulation of chemical synaptic transmission / negative regulation of MAPK cascade / protein tyrosine kinase activator activity / positive regulation of activated T cell proliferation / positive regulation of cardiac muscle hypertrophy / positive regulation of smooth muscle cell migration / positive regulation of axon regeneration / amyloid-beta clearance / negative regulation of release of cytochrome c from mitochondria / positive regulation of cytokinesis / positive regulation of osteoblast proliferation / negative regulation of amyloid-beta formation / negative regulation of smooth muscle cell apoptotic process / regulation of JNK cascade / estrous cycle / negative regulation of tumor necrosis factor production / insulin receptor substrate binding / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / G-protein alpha-subunit binding / Synthesis, secretion, and deacylation of Ghrelin / epithelial to mesenchymal transition / epidermis development / positive regulation of glycogen biosynthetic process / positive regulation of osteoblast differentiation / positive regulation of DNA binding / SHC-related events triggered by IGF1R / phosphatidylinositol 3-kinase binding / peptidyl-tyrosine autophosphorylation / positive regulation of tyrosine phosphorylation of STAT protein / positive regulation of vascular associated smooth muscle cell proliferation / cellular response to transforming growth factor beta stimulus / T-tubule / insulin-like growth factor receptor binding / activation of protein kinase B activity / transmembrane receptor protein tyrosine kinase activity / protein serine/threonine kinase activator activity / cerebellum development / positive regulation of glycolytic process / axonogenesis
Similarity search - Function
Insulin-like growth factor I / Insulin-like growth factor / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Insulin family / Insulin/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like ...Insulin-like growth factor I / Insulin-like growth factor / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Insulin family / Insulin/IGF/Relaxin family / Insulin, conserved site / Insulin family signature. / Insulin-like / Insulin / insulin-like growth factor / relaxin family. / Insulin-like superfamily / Receptor L-domain / Furin-like cysteine-rich domain / Receptor L-domain superfamily / Furin-like cysteine rich region / Receptor L domain / Furin-like repeat / Furin-like repeats / Growth factor receptor cysteine-rich domain superfamily / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Insulin-like growth factor I / Insulin-like growth factor 1 receptor
Similarity search - Component
Biological speciesMus musculus (house mouse) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.0 Å
AuthorsLi J / Wu JY / Hall C / Bai XC / Choi E
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM136976 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM142937 United States
CitationJournal: Elife / Year: 2022
Title: Molecular basis for the role of disulfide-linked αCTs in the activation of insulin-like growth factor 1 receptor and insulin receptor.
Authors: Jie Li / Jiayi Wu / Catherine Hall / Xiao-Chen Bai / Eunhee Choi /
Abstract: The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked ...The insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) control metabolic homeostasis and cell growth and proliferation. The IR and IGF1R form similar disulfide bonds linked homodimers in the apo-state; however, their ligand binding properties and the structures in the active state differ substantially. It has been proposed that the disulfide-linked C-terminal segment of α-chain (αCTs) of the IR and IGF1R control the cooperativity of ligand binding and regulate the receptor activation. Nevertheless, the molecular basis for the roles of disulfide-linked αCTs in IR and IGF1R activation are still unclear. Here, we report the cryo-EM structures of full-length mouse IGF1R/IGF1 and IR/insulin complexes with modified αCTs that have increased flexibility. Unlike the -shaped asymmetric IGF1R dimer with a single IGF1 bound, the IGF1R with the enhanced flexibility of αCTs can form a -shaped symmetric dimer with two IGF1s bound. Meanwhile, the IR with non-covalently linked αCTs predominantly adopts an asymmetric conformation with four insulins bound, which is distinct from the -shaped symmetric IR. Using cell-based experiments, we further showed that both IGF1R and IR with the modified αCTs cannot activate the downstream signaling potently. Collectively, our studies demonstrate that the certain structural rigidity of disulfide-linked αCTs is critical for optimal IR and IGF1R signaling activation.
History
DepositionOct 28, 2022-
Header (metadata) releaseNov 9, 2022-
Map releaseNov 9, 2022-
UpdateDec 7, 2022-
Current statusDec 7, 2022Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28693.png

Downloads & links

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Map

FileDownload / File: emd_28693.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation
Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.006
Minimum - Maximum-0.026597057 - 0.049789708
Average (Standard dev.)5.0296665e-05 (±0.0010395781)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 298.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Cryo-EM structure of two IGF1 bound full-length mouse...

Fileemd_28693_half_map_1.map
AnnotationCryo-EM structure of two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation Unfiltered half1 map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Cryo-EM structure of two IGF1 bound full-length mouse...

Fileemd_28693_half_map_2.map
AnnotationCryo-EM structure of two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation Unfiltered half2 map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Two IGF1 bound full-length mouse IGF1R mutant (four glycine resid...

EntireName: Two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation
Components
  • Complex: Two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation
    • Protein or peptide: Insulin-like growth factor 1 receptor
    • Protein or peptide: Insulin-like growth factor IInsulin-like growth factor 1

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Supramolecule #1: Two IGF1 bound full-length mouse IGF1R mutant (four glycine resid...

SupramoleculeName: Two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Mus musculus (house mouse)

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Macromolecule #1: Insulin-like growth factor 1 receptor

MacromoleculeName: Insulin-like growth factor 1 receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 144.481953 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EICGPGIDIR NDYQQLKRLE NCTVIEGFLH ILLISKAEDY RSYRFPKLTV ITEYLLLFRV AGLESLGDLF PNLTVIRGWK LFYNYALVI FEMTNLKDIG LYNLRNITRG AIRIEKNADL CYLSTIDWSL ILDAVSNNYI VGNKPPKECG DLCPGTLEEK P MCEKTTIN ...String:
EICGPGIDIR NDYQQLKRLE NCTVIEGFLH ILLISKAEDY RSYRFPKLTV ITEYLLLFRV AGLESLGDLF PNLTVIRGWK LFYNYALVI FEMTNLKDIG LYNLRNITRG AIRIEKNADL CYLSTIDWSL ILDAVSNNYI VGNKPPKECG DLCPGTLEEK P MCEKTTIN NEYNYRCWTT NRCQKMCPSV CGKRACTENN ECCHPECLGS CHTPDDNTTC VACRHYYYKG VCVPACPPGT YR FEGWRCV DRDFCANIPN AESSDSDGFV IHDDECMQEC PSGFIRNSTQ SMYCIPCEGP CPKVCGDEEK KTKTIDSVTS AQM LQGCTI LKGNLLINIR RGNNIASELE NFMGLIEVVT GYVKIRHSHA LVSLSFLKNL RLILGEEQLE GNYSFYVLDN QNLQ QLWDW NHRNLTVRSG KMYFAFNPKL CVSEIYRMEE VTGTKGRQSK GDINTRNNGE RASCESDVLR FTSTTTWKNR IIITW HRYR PPDYRDLISF TVYYKEAPFK NVTEYDGQDA CGSNSWNMVD VDLPPNKEGE PGILLHGLKP WTQYAVYVKA VTLTMV END HIRGAKSEIL YIRTNASVPS IPLDVLSASN SSSQLIVKWN PPTLPNGNLS YYIVRWQRQP QDGYLYRHNY CSKDKIP IR KYADGTIDVE EVTENPKTEV CGGDKGPCCA CPGGGGKTEA EKQAEKEEAE YRKVFENFLH NSIFVPRPER RRRDVMQV A NTTMSSRSRN TTVADTYNIT DPEEFETEYP FFESRVDNKE RTVISNLRPF TLYRIDIHSC NHEAEKLGCS ASNFVFART MPAEGADDIP GPVTWEPRPE NSIFLKWPEP ENPNGLILMY EIKYGSQVED QRECVSRQEY RKYGGAKLNR LNPGNYTARI QATSLSGNG SWTDPVFFYV PAKTTYENFM HLIIALPVAI LLIVGGLVIM LYVFHRKRNN SRLGNGVLYA SVNPEYFSAA D VYVPDEWE VAREKITMNR ELGQGSFGMV YEGVAKGVVK DEPETRVAIK TVNEAASMRE RIEFLNEASV MKEFNCHHVV RL LGVVSQG QPTLVIMELM TRGDLKSYLR SLRPEVEQNN LVLIPPSLSK MIQMAGEIAD GMAYLNANKF VHRDLAARNC MVA EDFTVK IGDFGMTRDI YETDYYRKGG KGLLPVRWMS PESLKDGVFT THSDVWSFGV VLWEIATLAE QPYQGLSNEQ VLRF VMEGG LLDKPDNCPD MLFELMRMCW QYNPKMRPSF LEIIGSIKDE MEPSFQEVSF YYSEENKPPE P

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Macromolecule #2: Insulin-like growth factor I

MacromoleculeName: Insulin-like growth factor I / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.88132 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGKISSLPTQ LFKCCFCDFL KVKMHTMSSS HLFYLALCLL TFTSSATAGP ETLCGAELVD ALQFVCGDRG FYFNKPTGYG SSSRRAPQT GIVDECCFRS CDLRRLEMYC APLKPAKSAR SVRAQRHTDM PKTQKYQPPS TNKNTKSQRR KGWPKTHPGG E QKEGTEAS ...String:
MGKISSLPTQ LFKCCFCDFL KVKMHTMSSS HLFYLALCLL TFTSSATAGP ETLCGAELVD ALQFVCGDRG FYFNKPTGYG SSSRRAPQT GIVDECCFRS CDLRRLEMYC APLKPAKSAR SVRAQRHTDM PKTQKYQPPS TNKNTKSQRR KGWPKTHPGG E QKEGTEAS LQIRGKKKEQ RREIGSRNAE CRGKKGK

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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

Concentration6 mg/mL
BufferpH: 7.4
GridModel: Quantifoil / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
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: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.6 µm
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 60.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1909017
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 4.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 21684

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