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- EMDB-24095: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand... -

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Basic information

Entry
Database: EMDB / ID: EMD-24095
TitleAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 648-1025 in complex with AUG-alpha
Map data
Samplehetero-tetrameric complex of anaplastic lymphoma kinase (ALK) with Augmentor alpha:
ALK tyrosine kinase receptor / ALK and LTK ligand 2
Function / homology
Function and homology information


positive regulation of ERK5 cascade / receptor signaling protein tyrosine kinase activator activity / response to environmental enrichment / swimming behavior / regulation of dopamine receptor signaling pathway / NF-kappaB-inducing kinase activity / positive regulation of dendrite development / regulation of neuron differentiation / adult behavior / neuron development ...positive regulation of ERK5 cascade / receptor signaling protein tyrosine kinase activator activity / response to environmental enrichment / swimming behavior / regulation of dopamine receptor signaling pathway / NF-kappaB-inducing kinase activity / positive regulation of dendrite development / regulation of neuron differentiation / adult behavior / neuron development / energy homeostasis / negative regulation of lipid catabolic process / phosphorylation / hippocampus development / positive regulation of neuron projection development / receptor tyrosine kinase binding / : / receptor protein-tyrosine kinase / positive regulation of kinase activity / regulation of cell population proliferation / transmembrane receptor protein tyrosine kinase signaling pathway / protein tyrosine kinase activity / regulation of apoptotic process / positive regulation of NF-kappaB transcription factor activity / transmembrane receptor protein tyrosine kinase activity / positive regulation of ERK1 and ERK2 cascade / receptor complex / protein autophosphorylation / signal transduction / integral component of plasma membrane / protein-containing complex / extracellular exosome / extracellular region / ATP binding / identical protein binding / plasma membrane
Similarity search - Function
ALK and LTK ligand FAM150 / FAM150 family / ALK tyrosine kinase receptor / MAM domain, meprin/A5/mu / MAM domain profile. / MAM domain / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Receptor tyrosine kinase class II signature. ...ALK and LTK ligand FAM150 / FAM150 family / ALK tyrosine kinase receptor / MAM domain, meprin/A5/mu / MAM domain profile. / MAM domain / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / Receptor tyrosine kinase class II signature. / Tyrosine-protein kinase, receptor class II, conserved site / Tyrosine kinase, catalytic domain / Tyrosine-protein kinase, catalytic domain / Concanavalin A-like lectin/glucanase domain superfamily / 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. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
ALK and LTK ligand 2 / ALK tyrosine kinase receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.27 Å
AuthorsMyasnikov AG / Reshetnyak AV / Kalodimos CG
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35 GM122462 United States
CitationJournal: Nature / Year: 2021
Title: Mechanism for the activation of the anaplastic lymphoma kinase receptor.
Authors: Andrey V Reshetnyak / Paolo Rossi / Alexander G Myasnikov / Munia Sowaileh / Jyotidarsini Mohanty / Amanda Nourse / Darcie J Miller / Irit Lax / Joseph Schlessinger / Charalampos G Kalodimos /
Abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system. The ALK gene is a hotspot for chromosomal translocation events ...Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that regulates important functions in the central nervous system. The ALK gene is a hotspot for chromosomal translocation events that result in several fusion proteins that cause a variety of human malignancies. Somatic and germline gain-of-function mutations in ALK were identified in paediatric neuroblastoma. ALK is composed of an extracellular region (ECR), a single transmembrane helix and an intracellular tyrosine kinase domain. ALK is activated by the binding of ALKAL1 and ALKAL2 ligands to its ECR, but the lack of structural information for the ALK-ECR or for ALKAL ligands has limited our understanding of ALK activation. Here we used cryo-electron microscopy, nuclear magnetic resonance and X-ray crystallography to determine the atomic details of human ALK dimerization and activation by ALKAL1 and ALKAL2. Our data reveal a mechanism of RTK activation that allows dimerization by either dimeric (ALKAL2) or monomeric (ALKAL1) ligands. This mechanism is underpinned by an unusual architecture of the receptor-ligand complex. The ALK-ECR undergoes a pronounced ligand-induced rearrangement and adopts an orientation parallel to the membrane surface. This orientation is further stabilized by an interaction between the ligand and the membrane. Our findings highlight the diversity in RTK oligomerization and activation mechanisms.
History
DepositionMay 24, 2021-
Header (metadata) releaseNov 24, 2021-
Map releaseNov 24, 2021-
UpdateDec 15, 2021-
Current statusDec 15, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.005
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.005
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  • Surface view with fitted model
  • Atomic models: PDB-7n00
  • Surface level: 0.005
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7n00
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Movie viewer
Structure viewerEM map:
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Supplemental images

Downloads & links

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Map

FileDownload / File: emd_24095.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 256 pix.
= 211.456 Å
0.83 Å/pix.
x 256 pix.
= 211.456 Å
0.83 Å/pix.
x 256 pix.
= 211.456 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.826 Å
Density
Contour LevelBy AUTHOR: 0.005 / Movie #1: 0.005
Minimum - Maximum-0.033018988 - 0.052078284
Average (Standard dev.)6.1926316e-06 (±0.0014943819)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 211.456 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8260.8260.826
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z211.456211.456211.456
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ260260260
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.0330.0520.000

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Supplemental data

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Additional map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...

Fileemd_24095_additional_1.map
AnnotationAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Additional map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...

Fileemd_24095_additional_2.map
AnnotationAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Additional map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...

Fileemd_24095_additional_3.map
AnnotationAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...

Fileemd_24095_half_map_1.map
AnnotationAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Half map: Anaplastic lymphoma kinase (ALK) extracellular fragment of ligand...

Fileemd_24095_half_map_2.map
AnnotationAnaplastic lymphoma kinase (ALK) extracellular fragment of ligand binding region 673-1025 in complex with AUG-alpha
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire hetero-tetrameric complex of anaplastic lymphoma kinase (ALK) wit...

EntireName: hetero-tetrameric complex of anaplastic lymphoma kinase (ALK) with Augmentor alpha
Number of Components: 3

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Component #1: protein, hetero-tetrameric complex of anaplastic lymphoma kinase ...

ProteinName: hetero-tetrameric complex of anaplastic lymphoma kinase (ALK) with Augmentor alpha
Recombinant expression: No
MassExperimental: 108 MDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli BL21(DE3) (bacteria)

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Component #2: protein, ALK tyrosine kinase receptor

ProteinName: ALK tyrosine kinase receptor / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 39.377559 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli BL21(DE3) (bacteria)

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Component #3: protein, ALK and LTK ligand 2

ProteinName: ALK and LTK ligand 2 / Number of Copies: 2 / Recombinant expression: No
MassTheoretical: 14.640013 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Escherichia coli BL21(DE3) (bacteria)

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Experimental details

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Sample preparation

SpecimenSpecimen State: Particle / Method: cryo EM
Sample solutionSpecimen conc.: 1 mg/mL / pH: 7.4
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen Name: ETHANE / Temperature: 283.15 K / Humidity: 95 %
Details: QUANTIFOIL R1.2/1/3 gold 300 mesh grids without glow-discharge, blotting time 3 sec., blotting force -5..

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS / Details: SerialEM coma-free alignment
Electron gunElectron Source: FIELD EMISSION GUN / Accelerating Voltage: 300 kV / Electron Dose: 81 e/Å2 / Illumination Mode: FLOOD BEAM
LensMagnification: 105000.0 X (nominal) / Cs: 2.7 mm / Imaging Mode: BRIGHT FIELD / Defocus: 500.0 - 1500.0 nm / Energy Filter: GIF Bioquantum
Specimen HolderModel: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature: (96.0 - 98.0 K)
CameraDetector: OTHER

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Image acquisition

Image acquisitionNumber of Digital Images: 2498 / Details: 4.2 second exposure, 70 frames, total dose 81e

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Image processing

ProcessingMethod: single particle reconstruction / Applied Symmetry: C2 (2 fold cyclic) / Number of Projections: 188516
3D reconstructionAlgorithm: FOURIER SPACE / Software: cryoSPARC / CTF correction: ctfFIND4 within Relion3.0 software / Resolution: 2.27 Å / Resolution Method: FSC 0.143 CUT-OFF / Details: cryoSPARC / Euler angles: as it is implemented in cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding

Modeling #1Refinement protocol: rigid body / Refinement space: REAL
Output model

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