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- PDB-8eyr: Cryo-EM structure of two IGF1 bound full-length mouse IGF1R mutan... -

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Basic information

Entry
Database: PDB / ID: 8eyr
TitleCryo-EM structure of two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation
Components
  • Insulin-like growth factor 1 receptor
  • Insulin-like growth factor I
KeywordsSIGNALING PROTEIN / IGF1R / IGF1
Function / homology
Function and homology information


negative regulation of cholangiocyte apoptotic process / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / SHC-related events triggered by IGF1R / glycolate metabolic process / muscle hypertrophy / negative regulation of oocyte development / insulin-like growth factor binding protein complex / insulin-like growth factor ternary complex / positive regulation of steroid hormone biosynthetic process ...negative regulation of cholangiocyte apoptotic process / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / SHC-related events triggered by IGF1R / glycolate metabolic process / muscle hypertrophy / negative regulation of oocyte development / insulin-like growth factor binding protein complex / insulin-like growth factor ternary complex / positive regulation of steroid hormone biosynthetic process / positive regulation of trophectodermal cell proliferation / positive regulation of type B pancreatic cell proliferation / prostate gland stromal morphogenesis / type II pneumocyte differentiation / negative regulation of muscle cell apoptotic process / proteoglycan biosynthetic process / neuronal dense core vesicle lumen / regulation of establishment or maintenance of cell polarity / chondroitin sulfate proteoglycan biosynthetic process / positive regulation of transcription regulatory region DNA binding / insulin-like growth factor receptor activity / positive regulation of DNA metabolic process / protein kinase complex / myotube cell development / Extra-nuclear estrogen signaling / negative regulation of neuroinflammatory response / insulin-like growth factor binding / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / skeletal muscle satellite cell maintenance involved in skeletal muscle regeneration / IRS-related events triggered by IGF1R / positive regulation of cerebellar granule cell precursor proliferation / bone mineralization involved in bone maturation / positive regulation of cell growth involved in cardiac muscle cell development / negative regulation of vascular associated smooth muscle cell apoptotic process / lung vasculature development / positive regulation of myoblast proliferation / exocytic vesicle / cerebellar granule cell precursor proliferation / protein transporter activity / positive regulation of glycoprotein biosynthetic process / positive regulation of axon regeneration / transcytosis / lung lobe morphogenesis / positive regulation of meiotic cell cycle / cell activation / negative regulation of hepatocyte apoptotic process / positive regulation of myelination / prostate gland epithelium morphogenesis / positive regulation of calcineurin-NFAT signaling cascade / positive regulation of developmental growth / negative regulation of androgen receptor signaling pathway / transmembrane receptor protein tyrosine kinase activator activity / glial cell differentiation / prostate gland growth / male sex determination / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / mammary gland development / positive regulation of protein-containing complex disassembly / exocrine pancreas development / alphav-beta3 integrin-IGF-1-IGF1R complex / myoblast differentiation / type B pancreatic cell proliferation / cell surface receptor signaling pathway via STAT / positive regulation of insulin-like growth factor receptor signaling pathway / regulation of nitric oxide biosynthetic process / positive regulation of Ras protein signal transduction / activation of protein kinase B activity / positive regulation of activated T cell proliferation / response to L-glutamate / dendritic spine maintenance / positive regulation of DNA binding / growth hormone receptor signaling pathway / regulation of JNK cascade / adrenal gland development / insulin binding / androgen receptor signaling pathway / negative regulation of interleukin-1 beta production / positive regulation of smooth muscle cell migration / muscle organ development / lung alveolus development / branching morphogenesis of an epithelial tube / cellular response to insulin-like growth factor stimulus / prostate epithelial cord arborization involved in prostate glandular acinus morphogenesis / positive regulation of osteoblast proliferation / negative regulation of release of cytochrome c from mitochondria / positive regulation of cytokinesis / positive regulation of cardiac muscle hypertrophy / establishment of cell polarity / inner ear development / negative regulation of amyloid-beta formation / type I pneumocyte differentiation / negative regulation of smooth muscle cell apoptotic process / amyloid-beta clearance / myoblast proliferation / insulin receptor substrate binding / Synthesis, secretion, and deacylation of Ghrelin / epithelial to mesenchymal transition / negative regulation of tumor necrosis factor production
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-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site ...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-like / Insulin/IGF/Relaxin family / Insulin / insulin-like growth factor / relaxin family. / Insulin, conserved site / Insulin family signature. / 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 / Immunoglobulins / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Immunoglobulin-like / Sandwich / Mainly Beta
Similarity search - Domain/homology
Insulin-like growth factor 1 / Insulin-like growth factor 1 receptor
Similarity search - Component
Biological speciesMus musculus (house mouse)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsLi, J. / Wu, J.Y. / Hall, C. / Bai, X.C. / Choi, E.
Funding support United States, 2items
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, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 9, 2022Provider: repository / Type: Initial release
Revision 1.1Dec 7, 2022Group: 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.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Insulin-like growth factor 1 receptor
A: Insulin-like growth factor 1 receptor
C: Insulin-like growth factor I
D: Insulin-like growth factor I


Theoretical massNumber of molelcules
Total (without water)332,7274
Polymers332,7274
Non-polymers00
Water00
1


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

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Components

#1: Protein Insulin-like growth factor 1 receptor / Insulin-like growth factor I receptor / IGF-I receptor


Mass: 144481.953 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Igf1r / Production host: Homo sapiens (human)
References: UniProt: Q60751, receptor protein-tyrosine kinase
#2: Protein Insulin-like growth factor I / IGF-I / Mechano growth factor / MGF / Somatomedin-C


Mass: 21881.320 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IGF1, IBP1 / Production host: Escherichia coli (E. coli) / References: UniProt: P05019
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: Two IGF1 bound full-length mouse IGF1R mutant (four glycine residues inserted in the alpha-CT; IGF1R-P674G4): symmetric conformation
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Mus musculus (house mouse)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil
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: 2600 nm / Nominal defocus min: 1600 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487: / Classification: refinement
EM software
IDNameCategory
1RELIONparticle selection
2SerialEMimage acquisition
4GctfCTF correction
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1909017
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 21684 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00513953
ELECTRON MICROSCOPYf_angle_d0.71618923
ELECTRON MICROSCOPYf_dihedral_angle_d5.4611887
ELECTRON MICROSCOPYf_chiral_restr0.0462041
ELECTRON MICROSCOPYf_plane_restr0.0062459

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