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- EMDB-26185: Cryo-EM Structure of insulin receptor-related receptor (IRR) in a... -

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Basic information

Entry
Database: EMDB / ID: EMD-26185
TitleCryo-EM Structure of insulin receptor-related receptor (IRR) in active-state captured at pH 9. The 3D refinement was applied with C2 symmetry
Map dataCryo-EM Structure of insulin receptor-related receptor (IRR) in active-state captured at pH 9. The 3D refinement was applied with C2 symmetry.
Sample
  • Complex: Insulin receptor-related receptor (IRR) in active-state captured at pH 9
    • Protein or peptide: Insulin receptor-related protein
KeywordsReceptor tyrosine kinase / insulin receptor family / SIGNALING PROTEIN
Function / homology
Function and homology information


cellular response to alkaline pH / male sex determination / insulin receptor complex / insulin receptor activity / insulin receptor substrate binding / phosphatidylinositol 3-kinase binding / cell surface receptor protein tyrosine kinase signaling pathway / transmembrane receptor protein tyrosine kinase activity / receptor protein-tyrosine kinase / actin cytoskeleton organization ...cellular response to alkaline pH / male sex determination / insulin receptor complex / insulin receptor activity / insulin receptor substrate binding / phosphatidylinositol 3-kinase binding / cell surface receptor protein tyrosine kinase signaling pathway / transmembrane receptor protein tyrosine kinase activity / receptor protein-tyrosine kinase / actin cytoskeleton organization / protein autophosphorylation / receptor complex / axon / ATP binding / plasma membrane
Similarity search - Function
Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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 ...Tyrosine-protein kinase, insulin-like receptor / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / 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 receptor-related protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 Å
AuthorsWang LW / Hall C / Li J / Choi E / Bai XC
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: Nat Struct Mol Biol / Year: 2023
Title: Structural basis of the alkaline pH-dependent activation of insulin receptor-related receptor.
Authors: Liwei Wang / Catherine Hall / Jie Li / Eunhee Choi / Xiao-Chen Bai /
Abstract: The insulin receptor (IR) family is a subfamily of receptor tyrosine kinases that controls metabolic homeostasis and cell growth. Distinct from IR and insulin-like growth factor 1 receptor, whose ...The insulin receptor (IR) family is a subfamily of receptor tyrosine kinases that controls metabolic homeostasis and cell growth. Distinct from IR and insulin-like growth factor 1 receptor, whose activation requires ligand binding, insulin receptor-related receptor (IRR)-the third member of the IR family-is activated by alkaline pH. However, the molecular mechanism underlying alkaline pH-induced IRR activation remains unclear. Here, we present cryo-EM structures of human IRR in both neutral pH inactive and alkaline pH active states. Combined with mutagenesis and cellular assays, we show that, upon pH increase, electrostatic repulsion of the pH-sensitive motifs of IRR disrupts its autoinhibited state and promotes a scissor-like rotation between two protomers, leading to a T-shaped active conformation. Together, our study reveals an unprecedented alkaline pH-dependent activation mechanism of IRR, opening up opportunities to understand the structure-function relationship of this important receptor.
History
DepositionFeb 13, 2022-
Header (metadata) releaseFeb 15, 2023-
Map releaseFeb 15, 2023-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_26185.png

Downloads & links

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Map

FileDownload / File: emd_26185.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM Structure of insulin receptor-related receptor (IRR) in active-state captured at pH 9. The 3D refinement was applied with C2 symmetry.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 300 pix.
= 324. Å		1.08 Å/pix.
x 300 pix.
= 324. Å		1.08 Å/pix.
x 300 pix.
= 324. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.08 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.09048769 - 0.14995372
Average (Standard dev.)0.000062892315 (±0.0034177331)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 324.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Insulin receptor-related receptor (IRR) in active-state captured ...

EntireName: Insulin receptor-related receptor (IRR) in active-state captured at pH 9
Components
  • Complex: Insulin receptor-related receptor (IRR) in active-state captured at pH 9
    • Protein or peptide: Insulin receptor-related protein

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Supramolecule #1: Insulin receptor-related receptor (IRR) in active-state captured ...

SupramoleculeName: Insulin receptor-related receptor (IRR) in active-state captured at pH 9
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 140 KDa

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Macromolecule #1: Insulin receptor-related protein

MacromoleculeName: Insulin receptor-related protein / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 143.879547 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MAVPSLWPWG ACLPVIFLSL GFGLDTVEVC PSLDIRSEVA ELRQLENCSV VEGHLQILLM FTATGEDFRG LSFPRLTQVT DYLLLFRVY GLESLRDLFP NLAVIRGTRL FLGYALVIFE MPHLRDVALP ALGAVLRGAV RVEKNQELCH LSTIDWGLLQ P APGANHIV ...String:
MAVPSLWPWG ACLPVIFLSL GFGLDTVEVC PSLDIRSEVA ELRQLENCSV VEGHLQILLM FTATGEDFRG LSFPRLTQVT DYLLLFRVY GLESLRDLFP NLAVIRGTRL FLGYALVIFE MPHLRDVALP ALGAVLRGAV RVEKNQELCH LSTIDWGLLQ P APGANHIV GNKLGEECAD VCPGVLGAAG EPCAKTTFSG HTDYRCWTSS HCQRVCPCPH GMACTARGEC CHTECLGGCS QP EDPRACV ACRHLYFQGA CLWACPPGTY QYESWRCVTA ERCASLHSVP GRASTFGIHQ GSCLAQCPSG FTRNSSSIFC HKC EGLCPK ECKVGTKTID SIQAAQDLVG CTHVEGSLIL NLRQGYNLEP QLQHSLGLVE TITGFLKIKH SFALVSLGFF KNLK LIRGD AMVDGNYTLY VLDNQNLQQL GSWVAAGLTI PVGKIYFAFN PRLCLEHIYR LEEVTGTRGR QNKAEINPRT NGDRA ACQT RTLRFVSNVT EADRILLRWE RYEPLEARDL LSFIVYYKES PFQNATEHVG PDACGTQSWN LLDVELPLSR TQEPGV TLA SLKPWTQYAV FVRAITLTTE EDSPHQGAQS PIVYLRTLPA APTVPQDVIS TSNSSSHLLV RWKPPTQRNG NLTYYLV LW QRLAEDGDLY LNDYCHRGLR LPTSNNDPRF DGEDGDPEAE MESDCCPCQH PPPGQVLPPL EAQEASFQKK FENFLHNA I TIPISPWKVT SINKSPQRDS GRHRRAAGPL RLGGNSSDFE IQEDKVPRER AVLSGLRHFT EYRIDIHACN HAAHTVGCS AATFVFARTM PHREADGIPG KVAWEASSKN SVLLRWLEPP DPNGLILKYE IKYRRLGEEA TVLCVSRLRY AKFGGVHLAL LPPGNYSAR VRATSLAGNG SWTDSVAFYI LGPEEEDAGG LHVLLTATPV GLTLLIVLAA LGFFYGKKRN RTLYASVNPE Y FSASDMYV PDEWEVPREQ ISIIRELGQG SFGMVYEGLA RGLEAGEEST PVALKTVNEL ASPRECIEFL KEASVMKAFK CH HVVRLLG VVSQGQPTLV IMELMTRGDL KSHLRSLRPE AENNPGLPQP ALGEMIQMAG EIADGMAYLA ANKFVHRDLA ARN CMVSQD FTVKIGDFGM TRDVYETDYY RKGGKGLLPV RWMAPESLKD GIFTTHSDVW SFGVVLWEIV TLAEQPYQGL SNEQ VLKFV MDGGVLEELE GCPLQLQELM SRCWQPNPRL RPSFTHILDS IQEELRPSFR LLSFYYSPEC RGARGSLPTT DAEPD SSPT PRDCSPQNGG PGH

UniProtKB: Insulin receptor-related protein

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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: 9
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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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: 3034847
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.4 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION / Number images used: 79010
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: AB INITIO MODEL
Output model

PDB-7tym:
Cryo-EM Structure of insulin receptor-related receptor (IRR) in active-state captured at pH 9. The 3D refinement was applied with C2 symmetry

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