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- EMDB-41878: Cryo-EM structure of long form insulin receptor (IR-B) with four ... -

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Entry
Database: EMDB / ID: EMD-41878
TitleCryo-EM structure of long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation.
Map dataCryo-EM structure of long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation.
Sample
  • Complex: Long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation.
    • Protein or peptide: Insulin receptor
    • Protein or peptide: Insulin-like growth factor II
KeywordsInsulin receptor / IGF2 / RTK / SIGNALING PROTEIN
Function / homology
Function and homology information


spongiotrophoblast cell proliferation / negative regulation of muscle cell differentiation / positive regulation of skeletal muscle tissue growth / 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 / genomic imprinting / regulation of female gonad development / positive regulation of meiotic cell cycle ...spongiotrophoblast cell proliferation / negative regulation of muscle cell differentiation / positive regulation of skeletal muscle tissue growth / 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 / genomic imprinting / regulation of female gonad development / positive regulation of meiotic cell cycle / positive regulation of organ growth / insulin-like growth factor II binding / positive regulation of developmental growth / male sex determination / exocrine pancreas development / insulin receptor complex / insulin-like growth factor I binding / insulin receptor activity / positive regulation of multicellular organism growth / 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 / adrenal gland development / activation of protein kinase activity / Signaling by Insulin receptor / IRS activation / transmembrane receptor protein tyrosine kinase activator activity / neuronal cell body membrane / positive regulation of activated T cell proliferation / positive regulation of respiratory burst / positive regulation of receptor internalization / positive regulation of cell division / amyloid-beta clearance / regulation of embryonic development / insulin receptor substrate binding / transport across blood-brain barrier / positive regulation of glycogen biosynthetic process / epidermis development / embryonic placenta development / SHC-related events triggered by IGF1R / Signal attenuation / phosphatidylinositol 3-kinase binding / heart morphogenesis / positive regulation of insulin receptor signaling pathway / Insulin receptor recycling / striated muscle cell differentiation / insulin-like growth factor receptor binding / dendrite membrane / neuron projection maintenance / activation of protein kinase B activity / positive regulation of glycolytic process / Insulin receptor signalling cascade / positive regulation of mitotic nuclear division / receptor-mediated endocytosis / protein serine/threonine kinase activator activity / insulin-like growth factor receptor signaling pathway / platelet alpha granule lumen / learning / positive regulation of D-glucose import / animal organ morphogenesis / insulin receptor binding / growth factor activity / positive regulation of MAP kinase activity / receptor protein-tyrosine kinase / caveola / cellular response to growth factor stimulus / receptor internalization / hormone activity / memory / peptidyl-tyrosine phosphorylation / cellular response to insulin stimulus / osteoblast differentiation / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / male gonad development / glucose metabolic process / positive regulation of nitric oxide biosynthetic process / late endosome / integrin binding / Platelet degranulation / insulin receptor signaling pathway / glucose homeostasis / amyloid-beta binding / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / protein tyrosine kinase activity / in utero embryonic development / protein autophosphorylation / positive regulation of MAPK cascade / lysosome / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor complex / endosome membrane / receptor ligand activity / positive regulation of cell migration / symbiont entry into host cell / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / 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-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 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 / 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 / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Insulin-like growth factor II / Insulin receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsAn W / Hall C / Li J / Huang A / Wu J / Park J / Bai XC / Choi E
Funding support United States, 1 items
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
DepositionSep 10, 2023-
Header (metadata) releaseMar 27, 2024-
Map releaseMar 27, 2024-
UpdateApr 3, 2024-
Current statusApr 3, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41878.png

Downloads & links

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Map

FileDownload / File: emd_41878.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation.
Projections & slices

Image control

Size
Brightness
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Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 360 pix.
= 388.8 Å		1.08 Å/pix.
x 360 pix.
= 388.8 Å		1.08 Å/pix.
x 360 pix.
= 388.8 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.006
Minimum - Maximum-0.019203844 - 0.03207199
Average (Standard dev.)-0.0000065669055 (±0.0006729276)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 388.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Cryo-EM structure of long form insulin receptor (IR-B)...

Fileemd_41878_half_map_1.map
AnnotationCryo-EM structure of long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation. Half map 1.
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: Cryo-EM structure of long form insulin receptor (IR-B)...

Fileemd_41878_half_map_2.map
AnnotationCryo-EM structure of long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation. Half map 2.
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Long form insulin receptor (IR-B) with four IGF2 bound, symmetric...

EntireName: Long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation.
Components
  • Complex: Long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation.
    • Protein or peptide: Insulin receptor
    • Protein or peptide: Insulin-like growth factor II

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Supramolecule #1: Long form insulin receptor (IR-B) with four IGF2 bound, symmetric...

SupramoleculeName: Long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Insulin receptor

MacromoleculeName: Insulin receptor / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 156.518328 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MATGGRRGAA AAPLLVAVAA LLLGAAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLL LFRVYGLESL KDLFPNLTVI RGSRLFFNYA LVIFEMVHLK ELGLYNLMNI TRGSVRIEKN NELCYLATID W SRILDSVE ...String:
MATGGRRGAA AAPLLVAVAA LLLGAAGHLY PGEVCPGMDI RNNLTRLHEL ENCSVIEGHL QILLMFKTRP EDFRDLSFPK LIMITDYLL LFRVYGLESL KDLFPNLTVI RGSRLFFNYA LVIFEMVHLK ELGLYNLMNI TRGSVRIEKN NELCYLATID W SRILDSVE DNYIVLNKDD NEECGDICPG TAKGKTNCPA TVINGQFVER CWTHSHCQKV CPTICKSHGC TAEGLCCHSE CL GNCSQPD DPTKCVACRN FYLDGRCVET CPPPYYHFQD WRCVNFSFCQ DLHHKCKNSR RQGCHQYVIH NNKCIPECPS GYT MNSSNL LCTPCLGPCP KVCHLLEGEK TIDSVTSAQE LRGCTVINGS LIINIRGGNN LAAELEANLG LIEEISGYLK IRRS YALVS LSFFRKLRLI RGETLEIGNY SFYALDNQNL RQLWDWSKHN LTITQGKLFF HYNPKLCLSE IHKMEEVSGT KGRQE RNDI ALKTNGDQAS CENELLKFSY IRTSFDKILL RWEPYWPPDF RDLLGFMLFY KEAPYQNVTE FDGQDACGSN SWTVVD IDP PLRSNDPKSQ NHPGWLMRGL KPWTQYAIFV KTLVTFSDER RTYGAKSDII YVQTDATNPS VPLDPISVSN SSSQIIL KW KPPSDPNGNI THYLVFWERQ AEDSELFELD YCLKGLKLPS RTWSPPFESE DSQKHNQSEY EDSAGECCSC PKTDSQIL K ELEESSFRKT FEDYLHNVVF VPRKTSSGTG AEDPRPSRKR RSLGDVGNVT VAVPTVAAFP NTSSTSVPTS PEEHRPFEK VVNKESLVIS GLRHFTGYRI ELQACNQDTP EERCSVAAYV SARTMPEAKA DDIVGPVTHE IFENNVVHLM WQEPKEPNGL IVLYEVSYR RYGDEELHLC VSRKHFALER GCRLRGLSPG NYSVRIRATS LAGNGSWTEP TYFYVTDYLD VPSNIAKIII G PLIFVFLF SVVIGSIYLF LRKRQPDGPL GPLYASSNPE YLSASDVFPC SVYVPDEWEV SREKITLLRE LGQGSFGMVY EG NARDIIK GEAETRVAVK TVNESASLRE RIEFLNEASV MKGFTCHHVV RLLGVVSKGQ PTLVVMELMA HGDLKSYLRS LRP EAENNP GRPPPTLQEM IQMAAEIADG MAYLNAKKFV HRDLAARNCM VAHDFTVKIG DFGMTRDIYE TDYYRKGGKG LLPV RWMAP ESLKDGVFTT SSDMWSFGVV LWEITSLAEQ PYQGLSNEQV LKFVMDGGYL DQPDNCPERV TDLMRMCWQF NPKMR PTFL EIVNLLKDDL HPSFPEVSFF HSEENKAPES EELEMEFEDM ENVPLDRSSH CQREEAGGRD GGSSLGFKRS YEEHIP YTH MNGGKKNGRI LTLPRSNPS

UniProtKB: Insulin receptor

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Macromolecule #2: Insulin-like growth factor II

MacromoleculeName: Insulin-like growth factor II / type: protein_or_peptide / ID: 2 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 20.170398 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MGIPMGKSML VLLTFLAFAS CCIAAYRPSE TLCGGELVDT LQFVCGDRGF YFSRPASRVS RRSRGIVEEC CFRSCDLALL ETYCATPAK SERDVSTPPT VLPDNFPRYP VGKFFQYDTW KQSTQRLRRG LPALLRARRG HVLAKELEAF REAKRHRPLI A LPTQDPAH GGAPPEMASN RK

UniProtKB: Insulin-like growth factor II

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.6 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3962294
Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C2 (2 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 74973
Initial angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final angle assignmentType: PROJECTION MATCHING / Software - Name: RELION
Final 3D classificationSoftware - Name: RELION

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-8u4c:
Cryo-EM structure of long form insulin receptor (IR-B) with four IGF2 bound, symmetric conformation.

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