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- PDB-8vjc: Cryo-EM structure of short form insulin receptor (IR-A) with thre... -

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Basic information

Entry
Database: PDB / ID: 8vjc
TitleCryo-EM structure of short form insulin receptor (IR-A) with three IGF2 bound, asymmetric conformation.
Components
  • Insulin-like growth factor IIInsulin-like growth factor 2
  • Isoform Short of Insulin receptor
KeywordsSIGNALING PROTEIN / Insulin receptor / IGF2 / RTK
Function / homology
Function and homology information


spongiotrophoblast cell proliferation / positive regulation of skeletal muscle tissue growth / negative regulation of muscle cell differentiation / embryonic placenta morphogenesis / regulation of muscle cell differentiation / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / regulation of female gonad development / genomic imprinting / positive regulation of meiotic cell cycle ...spongiotrophoblast cell proliferation / positive regulation of skeletal muscle tissue growth / negative regulation of muscle cell differentiation / embryonic placenta morphogenesis / regulation of muscle cell differentiation / Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R) / IRS-related events triggered by IGF1R / regulation of female gonad development / genomic imprinting / positive regulation of meiotic cell cycle / positive regulation of organ growth / positive regulation of developmental growth / insulin-like growth factor II binding / male sex determination / exocrine pancreas development / insulin receptor complex / insulin-like growth factor I binding / positive regulation of multicellular organism growth / insulin receptor activity / positive regulation of protein-containing complex disassembly / cargo receptor activity / positive regulation of vascular endothelial cell proliferation / dendritic spine maintenance / insulin binding / PTB domain binding / neuronal cell body membrane / adrenal gland development / Signaling by Insulin receptor / IRS activation / positive regulation of activated T cell proliferation / transmembrane receptor protein tyrosine kinase activator activity / amyloid-beta clearance / activation of protein kinase activity / positive regulation of respiratory burst / regulation of embryonic development / positive regulation of receptor internalization / positive regulation of cell division / transport across blood-brain barrier / insulin receptor substrate binding / embryonic placenta development / epidermis development / positive regulation of glycogen biosynthetic process / SHC-related events triggered by IGF1R / Signal attenuation / phosphatidylinositol 3-kinase binding / heart morphogenesis / positive regulation of insulin receptor signaling pathway / dendrite membrane / striated muscle cell differentiation / Insulin receptor recycling / insulin-like growth factor receptor binding / receptor-mediated endocytosis / neuron projection maintenance / activation of protein kinase B activity / positive regulation of glycolytic process / protein serine/threonine kinase activator activity / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / insulin-like growth factor receptor signaling pathway / platelet alpha granule lumen / learning / caveola / positive regulation of glucose import / animal organ morphogenesis / growth factor activity / positive regulation of MAP kinase activity / insulin receptor binding / hormone activity / receptor internalization / receptor protein-tyrosine kinase / memory / cellular response to growth factor stimulus / osteoblast differentiation / peptidyl-tyrosine phosphorylation / cellular response to insulin stimulus / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / male gonad development / cell surface receptor protein tyrosine kinase signaling pathway / glucose metabolic process / positive regulation of nitric oxide biosynthetic process / positive regulation of peptidyl-tyrosine phosphorylation / integrin binding / late endosome / glucose homeostasis / Platelet degranulation / insulin receptor signaling pathway / amyloid-beta binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / in utero embryonic development / positive regulation of MAPK cascade / protein autophosphorylation / lysosome / receptor ligand activity / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome membrane / carbohydrate metabolic process / positive regulation of cell migration / positive regulation of protein phosphorylation
Similarity search - Function
Insulin-like growth factor II E-peptide, C-terminal / Insulin-like growth factor II / Insulin-like growth factor II E-peptide / Insulin-like growth factor / Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Insulin family ...Insulin-like growth factor II E-peptide, C-terminal / Insulin-like growth factor II / Insulin-like growth factor II E-peptide / Insulin-like growth factor / Insulin receptor, trans-membrane domain / Insulin receptor trans-membrane segment / 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 III domain / 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 II / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsAn, W. / Hall, C. / Li, J. / Huang, A. / Wu, J. / Park, J. / Bai, X.C. / Choi, E.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM136976 United States
CitationJournal: Nat Commun / Year: 2024
Title: Activation of the insulin receptor by insulin-like growth factor 2.
Authors: Weidong An / Catherine Hall / Jie Li / Albert Hung / Jiayi Wu / Junhee Park / Liwei Wang / Xiao-Chen Bai / Eunhee Choi /
Abstract: Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin's function. However, the molecular ...Insulin receptor (IR) controls growth and metabolism. Insulin-like growth factor 2 (IGF2) has different binding properties on two IR isoforms, mimicking insulin's function. However, the molecular mechanism underlying IGF2-induced IR activation remains unclear. Here, we present cryo-EM structures of full-length human long isoform IR (IR-B) in both the inactive and IGF2-bound active states, and short isoform IR (IR-A) in the IGF2-bound active state. Under saturated IGF2 concentrations, both the IR-A and IR-B adopt predominantly asymmetric conformations with two or three IGF2s bound at site-1 and site-2, which differs from that insulin saturated IR forms an exclusively T-shaped symmetric conformation. IGF2 exhibits a relatively weak binding to IR site-2 compared to insulin, making it less potent in promoting full IR activation. Cell-based experiments validated the functional importance of IGF2 binding to two distinct binding sites in optimal IR signaling and trafficking. In the inactive state, the C-terminus of α-CT of IR-B contacts FnIII-2 domain of the same protomer, hindering its threading into the C-loop of IGF2, thus reducing the association rate of IGF2 with IR-B. Collectively, our studies demonstrate the activation mechanism of IR by IGF2 and reveal the molecular basis underlying the different affinity of IGF2 to IR-A and IR-B.
History
DepositionJan 6, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 27, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 3, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Isoform Short of Insulin receptor
B: Isoform Short of Insulin receptor
C: Insulin-like growth factor II
D: Insulin-like growth factor II
E: Insulin-like growth factor II


Theoretical massNumber of molelcules
Total (without water)371,1695
Polymers371,1695
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Isoform Short of Insulin receptor / IR


Mass: 155329.094 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: INSR / Production host: Homo sapiens (human)
References: UniProt: P06213, receptor protein-tyrosine kinase
#2: Protein Insulin-like growth factor II / Insulin-like growth factor 2


Mass: 20170.398 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: IGF2 / Production host: Escherichia coli (E. coli) / References: UniProt: P01344

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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: Short form insulin receptor (IR-A) with three IGF2 bound, asymmetric conformation.
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
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 FIELDBright-field microscopy / Nominal defocus max: 2600 nm / Nominal defocus min: 1600 nm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
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

EM software
IDNameCategory
1RELIONparticle selection
2SerialEMimage acquisition
4GctfCTF correction
7Cootmodel fitting
9PHENIXmodel refinement
10RELIONinitial Euler assignment
11RELIONfinal Euler assignment
12RELIONclassification
13RELION3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 3422813
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 79813 / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL

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