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- EMDB-25715: Structure of active Janus Kinase (JAK) dimer complexed with cytok... -

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Entry
Database: EMDB / ID: EMD-25715
TitleStructure of active Janus Kinase (JAK) dimer complexed with cytokine receptor intracellular domain
Map dataPhenix local anisotropic sharpened map based on half maps, cropped. An uncropped map was used for Phenix real-space refinement.
Sample
  • Complex: GCN4-zippered dimeric IFN-lambda intracellular domain bound to two Jak1s
    • Protein or peptide: Tyrosine-protein kinase
    • Protein or peptide: Interferon lambda receptor 1
  • Ligand: ADENOSINE
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
Keywordssignaling complex / Janus Kinase / JAK / oncogenic mutation / gain-of-function mutation / cytokine receptor / SIGNALING PROTEIN
Function / homology
Function and homology information


response to type III interferon / interleukin-28 receptor complex / Interleukin-20 family signaling / mucosal immune response / positive regulation of cellular respiration / protein localization to cell-cell junction / interleukin-11-mediated signaling pathway / CCR5 chemokine receptor binding / positive regulation of homotypic cell-cell adhesion / interleukin-9-mediated signaling pathway ...response to type III interferon / interleukin-28 receptor complex / Interleukin-20 family signaling / mucosal immune response / positive regulation of cellular respiration / protein localization to cell-cell junction / interleukin-11-mediated signaling pathway / CCR5 chemokine receptor binding / positive regulation of homotypic cell-cell adhesion / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / interleukin-2-mediated signaling pathway / regulation of defense response to virus by host / interleukin-15-mediated signaling pathway / growth hormone receptor binding / cytokine receptor activity / interleukin-6-mediated signaling pathway / type I interferon-mediated signaling pathway / positive regulation of sprouting angiogenesis / cell surface receptor signaling pathway via JAK-STAT / growth hormone receptor signaling pathway via JAK-STAT / endomembrane system / type II interferon-mediated signaling pathway / extrinsic component of cytoplasmic side of plasma membrane / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / cytokine-mediated signaling pathway / positive regulation of protein localization to nucleus / protein phosphatase binding / defense response to virus / cell differentiation / cytoskeleton / intracellular signal transduction / phosphorylation / response to antibiotic / ubiquitin protein ligase binding / ATP binding / nucleus / cytosol
Similarity search - Function
Tyrosine-protein kinase, non-receptor Jak1 / Tissue factor / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain / FERM central domain ...Tyrosine-protein kinase, non-receptor Jak1 / Tissue factor / Tyrosine-protein kinase, non-receptor Jak/Tyk2 / JAK, FERM F2 lobe domain / FERM F1 lobe ubiquitin-like domain / JAK1-3/TYK2, pleckstrin homology-like domain / Jak1 pleckstrin homology-like domain / FERM F2 acyl-CoA binding protein-like domain / FERM F1 ubiquitin-like domain / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain 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
Tyrosine-protein kinase / Interferon lambda receptor 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsGlassman CR / Tsutsumi N / Jude KM / Garcia KC
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R37AI051321 United States
Howard Hughes Medical Institute (HHMI) United States
Ludwig Institute for Cancer Research (LICR) United States
CitationJournal: Science / Year: 2022
Title: Structure of a Janus kinase cytokine receptor complex reveals the basis for dimeric activation.
Authors: Caleb R Glassman / Naotaka Tsutsumi / Robert A Saxton / Patrick J Lupardus / Kevin M Jude / K Christopher Garcia /
Abstract: Cytokines signal through cell surface receptor dimers to initiate activation of intracellular Janus kinases (JAKs). We report the 3.6-angstrom-resolution cryo-electron microscopy structure of full- ...Cytokines signal through cell surface receptor dimers to initiate activation of intracellular Janus kinases (JAKs). We report the 3.6-angstrom-resolution cryo-electron microscopy structure of full-length JAK1 complexed with a cytokine receptor intracellular domain Box1 and Box2 regions captured as an activated homodimer bearing the valine→phenylalanine (VF) mutation prevalent in myeloproliferative neoplasms. The seven domains of JAK1 form an extended structural unit, the dimerization of which is mediated by close-packing of the pseudokinase (PK) domains from the monomeric subunits. The oncogenic VF mutation lies within the core of the JAK1 PK interdimer interface, enhancing packing complementarity to facilitate ligand-independent activation. The carboxy-terminal tyrosine kinase domains are poised for transactivation and to phosphorylate the receptor STAT (signal transducer and activator of transcription)-recruiting motifs projecting from the overhanging FERM (four-point-one, ezrin, radixin, moesin)-SH2 (Src homology 2)-domains. Mapping of constitutively active JAK mutants supports a two-step allosteric activation mechanism and reveals opportunities for selective therapeutic targeting of oncogenic JAK signaling.
History
DepositionDec 13, 2021-
Header (metadata) releaseMar 16, 2022-
Map releaseMar 16, 2022-
UpdateFeb 28, 2024-
Current statusFeb 28, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.08
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.08
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7t6f
  • Surface level: 0.08
  • Imaged by UCSF Chimera
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Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_25715.png

Downloads & links

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Map

FileDownload / File: emd_25715.map.gz / Format: CCP4 / Size: 14.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPhenix local anisotropic sharpened map based on half maps, cropped. An uncropped map was used for Phenix real-space refinement.
Voxel sizeX=Y=Z: 0.8521 Å
Density
Contour LevelBy AUTHOR: 0.08 / Movie #1: 0.08
Minimum - Maximum-0.3418705 - 0.65219724
Average (Standard dev.)0.008276293 (±0.04772539)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin118109139
Dimensions164187123
Spacing123164187
CellA: 104.808304 Å / B: 139.7444 Å / C: 159.3427 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.852097560975610.852097560975610.85210160427807
M x/y/z123164187
origin x/y/z0.0000.0000.000
length x/y/z104.808139.744159.343
α/β/γ90.00090.00090.000
start NX/NY/NZ139118109
NX/NY/NZ123164187
MAP C/R/S321
start NC/NR/NS109118139
NC/NR/NS187164123
D min/max/mean-0.3420.6520.008

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Supplemental data

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Mask #1

Fileemd_25715_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
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Histogram (log scale)

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Mask #2

Fileemd_25715_msk_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Additional map: DeepEMhancer sharpened map with masking, cropped, for overall...

Fileemd_25715_additional_1.map
AnnotationDeepEMhancer sharpened map with masking, cropped, for overall map representation.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Additional map: Unsharpen full map.

Fileemd_25715_additional_2.map
AnnotationUnsharpen full map.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map A.

Fileemd_25715_half_map_1.map
AnnotationHalf map A.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half map B.

Fileemd_25715_half_map_2.map
AnnotationHalf map B.
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

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Sample components

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Entire : GCN4-zippered dimeric IFN-lambda intracellular domain bound to tw...

EntireName: GCN4-zippered dimeric IFN-lambda intracellular domain bound to two Jak1s
Components
  • Complex: GCN4-zippered dimeric IFN-lambda intracellular domain bound to two Jak1s
    • Protein or peptide: Tyrosine-protein kinase
    • Protein or peptide: Interferon lambda receptor 1
  • Ligand: ADENOSINE
  • Ligand: ADENOSINE-5'-DIPHOSPHATE

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Supramolecule #1: GCN4-zippered dimeric IFN-lambda intracellular domain bound to tw...

SupramoleculeName: GCN4-zippered dimeric IFN-lambda intracellular domain bound to two Jak1s
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Details: Co-expressed GST-fused GCN4-IFN-lambda and full-length Jak1 in T. ni. GST tagged was removed by 3C protease digestion.
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 290 KDa

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Macromolecule #1: Tyrosine-protein kinase

MacromoleculeName: Tyrosine-protein kinase / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: non-specific protein-tyrosine kinase
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 136.026844 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MQYLNIKEDC NAMAFCAKMR SFKKTEVKQV VPEPGVEVTF YLLDREPLRL GSGEYTAEEL CIRAAQECSI SPLCHNLFAL YDESTKLWY APNRIITVDD KTSLRLHYRM RFYFTNWHGT NDNEQSVWRH SPKKQKNGYE KKRVPEATPL LDASSLEYLF A QGQYDLIK ...String:
MQYLNIKEDC NAMAFCAKMR SFKKTEVKQV VPEPGVEVTF YLLDREPLRL GSGEYTAEEL CIRAAQECSI SPLCHNLFAL YDESTKLWY APNRIITVDD KTSLRLHYRM RFYFTNWHGT NDNEQSVWRH SPKKQKNGYE KKRVPEATPL LDASSLEYLF A QGQYDLIK CLAPIRDPKT EQDGHDIENE CLGMAVLAIS HYAMMKKMQL PELPKDISYK RYIPETLNKS IRQRNLLTRM RI NNVFKDF LKEFNNKTIC DSSVSTHDLK VKYLATLETL TKHYGAEIFE TSMLLISSEN ELSRCHSNDS GNVLYEVMVT GNL GIQWRQ KPNVVPVEKE KNKLKRKKLE YNKHKKDDER NKLREEWNNF SYFPEITHIV IKESVVSINK QDNKNMELKL SSRE EALSF VSLVDGYFRL TADAHHYLCT DVAPPLIVHN IQNGCHGPIC TEYAINKLRQ EGSEEGMYVL RWSCTDFDNI LMTVT CFEK SEVLGGQKQF KNFQIEVQKG RYSLHGSMDH FPSLRDLMNH LKKQILRTDN ISFVLKRCCQ PKPREISNLL VATKKA QEW QPVYSMSQLS FDRILKKDII QGEHLGRGTR THIYSGTLLD YKDEEGIAEE KKIKVILKVL DPSHRDISLA FFEAASM MR QVSHKHIVYL YGVCFRDVEN IMVEEFVEGG PLDLFMHRKS DALTTPWKFK VAKQLASALS YLEDKDLVHG NVCTKNLL L AREGIDSDIG PFIKLSDPGI PVSVLTRQEC IERIPWIAPE CVEDSKNLSV AADKWSFGTT LWEICYNGEI PLKDKTLIE KERFYESRCR PVTPSCKELA DLMTRCMNYD PNQRPFFRAI MRDINKLEEQ NPDIVSEKQP TTEVDPTHFE KRFLKRIRDL GEGHFGKVE LCRYDPEGDN TGEQVAVKSL KPESGGNHIA DLKKEIEILR NLYHENIVKY KGICMEDGGN GIKLIMEFLP S GSLKEYLP KNKNKINLKQ QLKYAIQICK GMDYLGSRQY VHRDLAARNV LVESEHQVKI GDFGLTKAIE TDKEYYTVKD DR DSPVFWY APECLIQCKF YIASDVWSFG VTLHELLTYC DSDFSPMALF LKMIGPTHGQ MTVTRLVNTL KEGKRLPCPP NCP DEVYQL MRKCWEFQPS NRTTFQNLIE GFEALLKGSD RKAAVSHWQH HHHHHHH

UniProtKB: Tyrosine-protein kinase

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Macromolecule #2: Interferon lambda receptor 1

MacromoleculeName: Interferon lambda receptor 1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 9.895373 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
GPRMKQLEDK VEELLSKNYH LENEVARLKK LVGERKIMKG NPWFQGVKTP RALDFSEYRY PVATFQPSGP EFSDDLILCP QKELT

UniProtKB: Interferon lambda receptor 1

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Macromolecule #3: ADENOSINE

MacromoleculeName: ADENOSINE / type: ligand / ID: 3 / Number of copies: 2 / Formula: ADN
Molecular weightTheoretical: 267.241 Da
Chemical component information

ChemComp-ADN:
ADENOSINE

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Macromolecule #4: ADENOSINE-5'-DIPHOSPHATE

MacromoleculeName: ADENOSINE-5'-DIPHOSPHATE / type: ligand / ID: 4 / Number of copies: 2 / Formula: ADP
Molecular weightTheoretical: 427.201 Da
Chemical component information

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

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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: 8
Component:
ConcentrationName
20.0 mMHepes-sodium salt
500.0 mMsodium chloride
1.0 % w/vglycerol
1.0 mMadenosine
1.0 mMTCEP

Details: additive: 0.01% w/v DDM
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 293 K / Instrument: LEICA EM GP / Details: 3 s blotting before plunging.
DetailsGCN4-mIFN-lambda-box1box2-mJak1 V657F

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: SUPER-RESOLUTION / Number grids imaged: 2 / Number real images: 29467 / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Calibrated magnification: 58680 / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 29000
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: 17057371
Details: Including non-proteinous features. The actual number of intact complex particles was ~1,429,325.
Startup modelType of model: OTHER
Details: The initial model was created by cryoSPARC ab-initio reconstruction with a C2 symmetry imposed.
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: cryoSPARC (ver. 3.3) / Number images used: 224615
Initial angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC (ver. 3.3)
Final angle assignmentType: ANGULAR RECONSTITUTION / Software - Name: cryoSPARC (ver. 3.3)
Final 3D classificationNumber classes: 2 / Software - Name: cryoSPARC (ver. 3.3)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-7t6f:
Structure of active Janus Kinase (JAK) dimer complexed with cytokine receptor intracellular domain

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