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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


Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / SHC-related events triggered by IGF1R / mitotic nuclear division / 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) / IRS-related events triggered by IGF1R / SHC-related events triggered by IGF1R / mitotic nuclear division / 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 / positive regulation of glycoprotein biosynthetic process / proteoglycan biosynthetic process / myotube cell development / Extra-nuclear estrogen signaling / negative regulation of neuroinflammatory response / positive regulation of transcription regulatory region DNA binding / 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 / bone mineralization involved in bone maturation / positive regulation of cell growth involved in cardiac muscle cell development / IRS-related events triggered by IGF1R / negative regulation of vascular associated smooth muscle cell apoptotic process / exocytic vesicle / positive regulation of meiotic cell cycle / positive regulation of developmental growth / cell activation / positive regulation of calcineurin-NFAT signaling cascade / prostate gland epithelium morphogenesis / male sex determination / exocrine pancreas development / mammary gland development / cell surface receptor signaling pathway via STAT / alphav-beta3 integrin-IGF-1-IGF1R complex / myoblast differentiation / positive regulation of Ras protein signal transduction / positive regulation of insulin-like growth factor receptor signaling pathway / myoblast proliferation / negative regulation of interleukin-1 beta production / positive regulation of DNA binding / adrenal gland development / muscle organ development / positive regulation of smooth muscle cell migration / positive regulation of cardiac muscle hypertrophy / negative regulation of release of cytochrome c from mitochondria / negative regulation of amyloid-beta formation / positive regulation of activated T cell proliferation / negative regulation of smooth muscle cell apoptotic process / insulin receptor substrate binding / negative regulation of tumor necrosis factor production / Synthesis, secretion, and deacylation of Ghrelin / epidermis development / epithelial to mesenchymal transition / positive regulation of glycogen biosynthetic process / phosphatidylinositol 3-kinase binding / postsynaptic modulation of chemical synaptic transmission / SHC-related events triggered by IGF1R / positive regulation of osteoblast differentiation / negative regulation of MAPK cascade / activation of protein kinase B activity / positive regulation of vascular associated smooth muscle cell proliferation / insulin-like growth factor receptor binding / T-tubule / phosphatidylinositol 3-kinase/protein kinase B signal transduction / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of mitotic nuclear division / insulin-like growth factor receptor signaling pathway / positive regulation of epithelial cell proliferation / platelet alpha granule lumen / positive regulation of glycolytic process / animal organ morphogenesis / skeletal system development / positive regulation of D-glucose import / negative regulation of extrinsic apoptotic signaling pathway / positive regulation of protein secretion / positive regulation of smooth muscle cell proliferation / insulin receptor binding / growth factor activity / wound healing / cellular response to glucose stimulus / placental growth factor receptor activity / insulin receptor activity / vascular endothelial growth factor receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / GPI-linked ephrin receptor activity / transmembrane-ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / brain development / hormone activity / cellular response to insulin stimulus
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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Immunoglobulin-like fold / Protein kinase domain profile. / Protein kinase domain / Immunoglobulins / 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

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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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