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- EMDB-44556: Structure of the extracellular domain of Protein Sevenless -

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Basic information

Entry
Database: EMDB / ID: EMD-44556
TitleStructure of the extracellular domain of Protein Sevenless
Map data
Sample
  • Cell: Protein sevenless
    • Protein or peptide: Protein sevenless
Keywordsreceptor tyrosine kinase / ROS1 / SIGNALING PROTEIN
Function / homology
Function and homology information


germ-line stem-cell niche homeostasis / transmembrane receptor protein kinase activity / R7 cell fate commitment / sevenless signaling pathway / regulation of TOR signaling / transmembrane receptor protein tyrosine kinase activity / visual perception / cell surface receptor protein tyrosine kinase signaling pathway / placental growth factor receptor activity / insulin receptor activity ...germ-line stem-cell niche homeostasis / transmembrane receptor protein kinase activity / R7 cell fate commitment / sevenless signaling pathway / regulation of TOR signaling / transmembrane receptor protein tyrosine kinase activity / visual perception / cell surface receptor protein tyrosine kinase signaling pathway / placental growth factor receptor activity / insulin receptor activity / hepatocyte growth factor receptor activity / macrophage colony-stimulating factor receptor activity / platelet-derived growth factor alpha-receptor activity / platelet-derived growth factor beta-receptor activity / stem cell factor receptor activity / boss receptor activity / protein tyrosine kinase collagen receptor activity / brain-derived neurotrophic factor receptor activity / transmembrane-ephrin receptor activity / GPI-linked ephrin receptor activity / epidermal growth factor receptor activity / fibroblast growth factor receptor activity / insulin-like growth factor receptor activity / receptor protein-tyrosine kinase / receptor complex / ATP binding / plasma membrane
Similarity search - Function
LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Six-bladed beta-propeller, TolB-like / Fibronectin type III domain / : / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III ...LDLR class B repeat / Low-density lipoprotein-receptor YWTD domain / Tyrosine-protein kinase, receptor class II, conserved site / Receptor tyrosine kinase class II signature. / Six-bladed beta-propeller, TolB-like / 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
Biological speciesDrosophila melanogaster (fruit fly)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.94 Å
AuthorsZhang J / Klein DE
Funding support1 items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2025
Title: Structural basis for the interaction between the Drosophila RTK Sevenless (dROS1) and the GPCR BOSS.
Authors: Jianan Zhang / Yuko Tsutsui / Hengyi Li / Tongqing Li / Yueyue Wang / Salma Laraki / Sofia Alarcon-Frias / Steven E Stayrook / Daryl E Klein /
Abstract: Sevenless, the Drosophila homologue of ROS1 (University of Rochester Sarcoma) (herein, dROS1) is a receptor tyrosine kinase (RTK) essential for the differentiation of Drosophila R7 photoreceptor ...Sevenless, the Drosophila homologue of ROS1 (University of Rochester Sarcoma) (herein, dROS1) is a receptor tyrosine kinase (RTK) essential for the differentiation of Drosophila R7 photoreceptor cells. Activation of dROS1 is mediated by binding to the extracellular region (ECR) of the GPCR (G protein coupled receptor) BOSS (Bride Of Sevenless) on adjacent cells. Activation of dROS1 by BOSS leads to subsequent downstream signaling pathways including SOS (Son of Sevenless). However, the physical basis for how dROS1 interacts with BOSS has long remained unknown. Here we provide a cryo-EM structure of dROS1's extracellular region, which mediates ligand binding. We show that the extracellular region of dROS1 adopts a folded-over conformation stabilized by an N-terminal domain comprised of two disulfide stapled helical hairpins. We further narrowed down the interacting binding epitopes on both dROS1 and BOSS using hydrogen-deuterium exchange mass spectrometry (HDX-MS). This includes beta-strands in dROS1's third Fibronectin type III (FNIII) domain and a C-terminal peptide in BOSS' ECR. Our mutagenesis studies, coupled with AlphaFold complex predictions, support a binding interaction mediated by a hydrophobic interaction and beta-strand augmentation between these regions. Our findings provide a fundamental understanding of the regulatory function of dROS1 and further provide mechanistic insight into the human ortholog and oncogene ROS1.
History
DepositionApr 22, 2024-
Header (metadata) releaseJan 22, 2025-
Map releaseJan 22, 2025-
UpdateFeb 5, 2025-
Current statusFeb 5, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_44556.png

Downloads & links

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Map

FileDownload / File: emd_44556.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 384 pix.
= 319.488 Å		0.83 Å/pix.
x 384 pix.
= 319.488 Å		0.83 Å/pix.
x 384 pix.
= 319.488 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.832 Å
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Histogram (log scale)
Contour LevelBy AUTHOR: 0.0804
Minimum - Maximum-0.5177348 - 0.90324557
Average (Standard dev.)0.00012509558 (±0.010272076)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 319.488 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_44556_msk_1.map
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Half map: #1

Fileemd_44556_half_map_1.map
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Half map: #2

Fileemd_44556_half_map_2.map
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Sample components

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Entire : Protein sevenless

EntireName: Protein sevenless
Components
  • Cell: Protein sevenless
    • Protein or peptide: Protein sevenless

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Supramolecule #1: Protein sevenless

SupramoleculeName: Protein sevenless / type: cell / ID: 1 / Parent: 0 / Macromolecule list: all / Details: Monomeric
Source (natural)Organism: Drosophila melanogaster (fruit fly)

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Macromolecule #1: Protein sevenless

MacromoleculeName: Protein sevenless / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: receptor protein-tyrosine kinase
Source (natural)Organism: Drosophila melanogaster (fruit fly)
Molecular weightTheoretical: 181.029219 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: HHHHHHHHGS STSNIEGRSR VTRDCVQRCI VEEDLFLDEF GIQCEKADNG EKCYKTRCTK GCAQWYRALK ELESCQEACL SLQFYPYDM PCIGACEMAQ RDYWHLQRLA ISHLVERTQP QLERAPRADG QSTPLTIRWA MHFPEHYLAS RPFNIQYQFV D HHGEELDL ...String:
HHHHHHHHGS STSNIEGRSR VTRDCVQRCI VEEDLFLDEF GIQCEKADNG EKCYKTRCTK GCAQWYRALK ELESCQEACL SLQFYPYDM PCIGACEMAQ RDYWHLQRLA ISHLVERTQP QLERAPRADG QSTPLTIRWA MHFPEHYLAS RPFNIQYQFV D HHGEELDL EQEDQDASGE TGSSAWFNLA DYDCDEYYVC EILEALIPYT QYRFRFELPF GENRDEVLYS PATPAYQTPP EG APISAPV IEHLMGLDDS HLAVHWHPGR FTNGPIEGYR LRLSSSEGNA TSEQLVPAGR GSYIFSQLQA GTNYTLALSM INK QGEGPV AKGFVQTHSA RNEKPAKDLT ESVLLVGRRA VMWQSLEPAG ENSMIYQSQE ELADIAWSKR EQQLWLLNVH GELR SLKFE SGQMVSPAQQ LKLDLGNISS GRWVPRRLSF DWLHHRLYFA MESPERNQSS FQIISTDLLG ESAQKVGESF DLPVE QLEV DALNGWIFWR NEESLWRQDL HGRMIHRLLR IRQPGWFLVQ PQHFIIHLML PQEGKFLEIS YDGGFKHPLP LPPPSN GAG NGPASSHWQS FALLGRSLLL PDSGQLILVE QQGQAASPSA SWPLKNLPDC WAVILLVPES QPLTSAGGKP HSLKALL GA QAAKISWKEP ERNPYQSADA ARSWSYELEV LDVASQSAFS IRNIRGPIFG LQRLQPDNLY QLRVRAINVD GEPGEWTE P LAARTWPLGP HRLRWASRQG SVIHTNELGE GLEVQQEQLE RLPGPMTMVN ESVGYYVTGD GLLHCINLVH SQWGCPISE PLQHVGSVTY DWRGGRVYWT DLARNCVVRM DPWSGSRELL PVFEANFLAL DPRQGHLYYA TSSQLSRHGS TPDEAVTYYR VNGLEGSIA SFVLDTQQDQ LFWLVKGSGA LRLYRAPLTA GGDSLQMIQQ IKGVFQAVPD SLQLLRPLGA LLWLERSGRR A RLVRLAAP LDVMELPTPD QASPASALQL LDPQPLPPRD EGVIPMTVLP DSVRLDDGHW DDFHVRWQPS TSGGNHSVSY RL LLEFGQR LQTLDLSTPF ARLTQLPQAQ LQLKISITPR TAWRSGDTTR VQLTTPPVAP SQPRRLRVFV ERLATALQEA NVS AVLRWD APEQGQEAPM QALEYHISCW VGSELHEELR LNQSALEARV EHLQPDQTYH FQVEARVAAT GAAAGAASHA LHVA PEVQA VPRVLYANAE FIGELDLDTR NRRRLVHTAS PVEHLVGIEG EQRLLWVNEH VELLTHVPGS APAKLARMRA EVLAL AVDW IQRIVYWAEL DATAPQAAII YRLDLCNFEG KILQGERVWS TPRGRLLKDL VALPQAQSLI WLEYEQGSPR NGSLRG RNL TDGSELEWAT VQPLIRLHAG SLEPGSETLN LVDNQGKLCV YDVARQLCTA SALRAQLNLL GEDSIAGQLA QDSGYLY AV KNWSIRAYGR RRQQLEYTVE LEPEEVRLLQ AHNYQAYPPK NCLLLPSSGG SLLKATDCEE QRCLLNLPMI TASEDCPL P IPGVRYQLNL TLARGPGSEE HDHGVEPLGQ WLLGAGESLN LTDLLPFTRY RVSGILSSFY QKKLALPTLV LAPLELLTA SATDYKDDDD K

UniProtKB: Protein sevenless

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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
Component:
ConcentrationNameFormula
20.0 mMHEPES
150.0 mMsodium chlorideNaCl
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 289.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.56 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.6 µm / Nominal defocus min: 1.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.94 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 144311
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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