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- EMDB-28649: Structure of Janus Kinase (JAK) dimer complexed with cytokine rec... -

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Entry
Database: EMDB / ID: EMD-28649
TitleStructure of Janus Kinase (JAK) dimer complexed with cytokine receptor intracellular domain
Map datasharpened map
Sample
  • Complex: Structure of Janus Kinase (JAK) dimer complexed with cytokine receptor intracellular domain
    • Protein or peptide: Tyrosine-protein kinase
    • Protein or peptide: Interferon lambda receptor 1
  • Ligand: ADENOSINE
  • Ligand: ADENOSINE-5'-DIPHOSPHATE
KeywordsJAK / Kinase / Cytokine / 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-10-mediated signaling pathway / CCR5 chemokine receptor binding / interleukin-11-mediated signaling pathway / 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-10-mediated signaling pathway / CCR5 chemokine receptor binding / interleukin-11-mediated signaling pathway / interleukin-9-mediated signaling pathway / interleukin-4-mediated signaling pathway / positive regulation of homotypic cell-cell adhesion / 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 / extrinsic component of cytoplasmic side of plasma membrane / type I interferon-mediated signaling pathway / interleukin-6-mediated signaling pathway / positive regulation of sprouting angiogenesis / cell surface receptor signaling pathway via JAK-STAT / type II interferon-mediated signaling pathway / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / positive regulation of protein localization to nucleus / protein phosphatase binding / defense response to virus / cytoskeleton / intracellular signal transduction / response to antibiotic / ubiquitin protein ligase binding / ATP binding / nucleus / cytoplasm
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 / : / SH2 domain / Jak1 pleckstrin homology-like 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 / : / SH2 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 / 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
Tyrosine-protein kinase / Interferon lambda receptor 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 5.5 Å
AuthorsCaveney NA / Saxton RA / Waghray D / Garcia KC
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R37AI51321 United States
CitationJournal: Cell Rep / Year: 2023
Title: Structural basis of Janus kinase trans-activation.
Authors: Nathanael A Caveney / Robert A Saxton / Deepa Waghray / Caleb R Glassman / Naotaka Tsutsumi / Stevan R Hubbard / K Christopher Garcia /
Abstract: Janus kinases (JAKs) mediate signal transduction downstream of cytokine receptors. Cytokine-dependent dimerization is conveyed across the cell membrane to drive JAK dimerization, trans- ...Janus kinases (JAKs) mediate signal transduction downstream of cytokine receptors. Cytokine-dependent dimerization is conveyed across the cell membrane to drive JAK dimerization, trans-phosphorylation, and activation. Activated JAKs in turn phosphorylate receptor intracellular domains (ICDs), resulting in the recruitment, phosphorylation, and activation of signal transducer and activator of transcription (STAT)-family transcription factors. The structural arrangement of a JAK1 dimer complex with IFNλR1 ICD was recently elucidated while bound by stabilizing nanobodies. While this revealed insights into the dimerization-dependent activation of JAKs and the role of oncogenic mutations in this process, the tyrosine kinase (TK) domains were separated by a distance not compatible with the trans-phosphorylation events between the TK domains. Here, we report the cryoelectron microscopy structure of a mouse JAK1 complex in a putative trans-activation state and expand these insights to other physiologically relevant JAK complexes, providing mechanistic insight into the crucial trans-activation step of JAK signaling and allosteric mechanisms of JAK inhibition.
History
DepositionOct 24, 2022-
Header (metadata) releaseMar 8, 2023-
Map releaseMar 8, 2023-
UpdateDec 25, 2024-
Current statusDec 25, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_28649.png

Downloads & links

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Map

FileDownload / File: emd_28649.map.gz / Format: CCP4 / Size: 8.8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationsharpened map
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
2.22 Å/pix.
x 132 pix.
= 292.544 Å		2.22 Å/pix.
x 132 pix.
= 292.544 Å		2.22 Å/pix.
x 132 pix.
= 292.544 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 2.21624 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.375
Minimum - Maximum-1.0783267 - 1.5835154
Average (Standard dev.)0.0027169774 (±0.060266905)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions132132132
Spacing132132132
CellA=B=C: 292.54398 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_28649_msk_1.map
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Half map: half map A

Fileemd_28649_half_map_1.map
Annotationhalf map A
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Half map: half map B

Fileemd_28649_half_map_2.map
Annotationhalf map B
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Sample components

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Entire : Structure of Janus Kinase (JAK) dimer complexed with cytokine rec...

EntireName: Structure of Janus Kinase (JAK) dimer complexed with cytokine receptor intracellular domain
Components
  • Complex: Structure of Janus Kinase (JAK) dimer complexed with cytokine receptor intracellular domain
    • 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: Structure of Janus Kinase (JAK) dimer complexed with cytokine rec...

SupramoleculeName: Structure of Janus Kinase (JAK) dimer complexed with cytokine receptor intracellular domain
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Mus musculus (house mouse)

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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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.6 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: OTHER / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 5.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 174962
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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