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- PDB-6ty3: FAK structure from single particle analysis of 2D crystals -

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Basic information

Entry
Database: PDB / ID: 6ty3
TitleFAK structure from single particle analysis of 2D crystals
ComponentsFocal adhesion kinase 1
KeywordsCELL ADHESION / Kinase / Focal Adhesion / Membrane
Function / homology
Function and homology information


Apoptotic cleavage of cellular proteins / NCAM signaling for neurite out-growth / RHO GTPases Activate WASPs and WAVEs / RAF/MAP kinase cascade / Regulation of actin dynamics for phagocytic cup formation / radial glia-guided pyramidal neuron migration / negative regulation of protein autophosphorylation / calcium-dependent cysteine-type endopeptidase activity / positive regulation of substrate-dependent cell migration, cell attachment to substrate / Integrin signaling ...Apoptotic cleavage of cellular proteins / NCAM signaling for neurite out-growth / RHO GTPases Activate WASPs and WAVEs / RAF/MAP kinase cascade / Regulation of actin dynamics for phagocytic cup formation / radial glia-guided pyramidal neuron migration / negative regulation of protein autophosphorylation / calcium-dependent cysteine-type endopeptidase activity / positive regulation of substrate-dependent cell migration, cell attachment to substrate / Integrin signaling / GRB2:SOS provides linkage to MAPK signaling for Integrins / DCC mediated attractive signaling / MET activates PTK2 signaling / Extra-nuclear estrogen signaling / EPHB-mediated forward signaling / p130Cas linkage to MAPK signaling for integrins / VEGFA-VEGFR2 Pathway / angiogenesis involved in wound healing / signal complex assembly / response to pH / negative regulation of cell-substrate adhesion / wound healing, spreading of cells / positive regulation of focal adhesion assembly / negative regulation of anoikis / positive regulation of protein tyrosine kinase activity / regulation of cell adhesion / response to muscle stretch / ciliary basal body / molecular function activator activity / actin filament organization / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / epidermal growth factor receptor signaling pathway / sarcolemma / integrin binding / positive regulation of protein binding / cell cortex / protein tyrosine kinase activity / protease binding / protein autophosphorylation / dendritic spine / positive regulation of cell migration / focal adhesion / centrosome / positive regulation of cell population proliferation / perinuclear region of cytoplasm / ATP binding / identical protein binding / nucleus / cytoplasm
Similarity search - Function
Focal adhesion kinase, targeting (FAT) domain / Focal adhesion kinase, targeting (FAT) domain superfamily / Focal adhesion kinase, N-terminal / FAK1/PYK2, FERM domain C-lobe / Focal adhesion targeting region / FERM N-terminal domain / : / FAK1/PYK2, FERM domain C-lobe / FERM domain signature 2. / FERM central domain ...Focal adhesion kinase, targeting (FAT) domain / Focal adhesion kinase, targeting (FAT) domain superfamily / Focal adhesion kinase, N-terminal / FAK1/PYK2, FERM domain C-lobe / Focal adhesion targeting region / FERM N-terminal domain / : / FAK1/PYK2, FERM domain C-lobe / FERM domain signature 2. / FERM central domain / FERM/acyl-CoA-binding protein superfamily / FERM central domain / FERM superfamily, second domain / FERM domain / FERM domain profile. / Band 4.1 domain / Band 4.1 homologues / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Ubiquitin-like domain superfamily / 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
Focal adhesion kinase 1
Similarity search - Component
Biological speciesGallus gallus (chicken)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 6.32 Å
AuthorsAcebron, I. / Righetto, R. / Biyani, N. / Chami, M. / Boskovic, J. / Stahlberg, H. / Lietha, D.
Funding support Spain, Switzerland, 2items
OrganizationGrant numberCountry
Spanish Ministry of Science, Innovation, and Universities Spain
Swiss National Science Foundation Switzerland
CitationJournal: EMBO J / Year: 2020
Title: Structural basis of Focal Adhesion Kinase activation on lipid membranes.
Authors: Iván Acebrón / Ricardo D Righetto / Christina Schoenherr / Svenja de Buhr / Pilar Redondo / Jayne Culley / Carlos F Rodríguez / Csaba Daday / Nikhil Biyani / Oscar Llorca / Adam Byron / ...Authors: Iván Acebrón / Ricardo D Righetto / Christina Schoenherr / Svenja de Buhr / Pilar Redondo / Jayne Culley / Carlos F Rodríguez / Csaba Daday / Nikhil Biyani / Oscar Llorca / Adam Byron / Mohamed Chami / Frauke Gräter / Jasminka Boskovic / Margaret C Frame / Henning Stahlberg / Daniel Lietha /
Abstract: Focal adhesion kinase (FAK) is a key component of the membrane proximal signaling layer in focal adhesion complexes, regulating important cellular processes, including cell migration, proliferation, ...Focal adhesion kinase (FAK) is a key component of the membrane proximal signaling layer in focal adhesion complexes, regulating important cellular processes, including cell migration, proliferation, and survival. In the cytosol, FAK adopts an autoinhibited state but is activated upon recruitment into focal adhesions, yet how this occurs or what induces structural changes is unknown. Here, we employ cryo-electron microscopy to reveal how FAK associates with lipid membranes and how membrane interactions unlock FAK autoinhibition to promote activation. Intriguingly, initial binding of FAK to the membrane causes steric clashes that release the kinase domain from autoinhibition, allowing it to undergo a large conformational change and interact itself with the membrane in an orientation that places the active site toward the membrane. In this conformation, the autophosphorylation site is exposed and multiple interfaces align to promote FAK oligomerization on the membrane. We show that interfaces responsible for initial dimerization and membrane attachment are essential for FAK autophosphorylation and resulting cellular activity including cancer cell invasion, while stable FAK oligomerization appears to be needed for optimal cancer cell proliferation in an anchorage-independent manner. Together, our data provide structural details of a key membrane bound state of FAK that is primed for efficient autophosphorylation and activation, hence revealing the critical event in integrin mediated FAK activation and signaling at focal adhesions.
History
DepositionJan 15, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 19, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 14, 2020Group: Database references / Category: citation / Item: _citation.journal_volume
Revision 1.2May 22, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_3d_fitting_list / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_3d_fitting_list.accession_code / _em_3d_fitting_list.initial_refinement_model_id / _em_3d_fitting_list.source_name / _em_3d_fitting_list.type

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Structure visualization

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Assembly

Deposited unit
A: Focal adhesion kinase 1
B: Focal adhesion kinase 1


Theoretical massNumber of molelcules
Total (without water)150,9532
Polymers150,9532
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area3160 Å2
ΔGint-13 kcal/mol
Surface area62780 Å2

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Components

#1: Protein Focal adhesion kinase 1 / FADK 1 / Focal adhesion kinase-related nonkinase / p41/p43FRNK / Protein-tyrosine kinase 2 / ...FADK 1 / Focal adhesion kinase-related nonkinase / p41/p43FRNK / Protein-tyrosine kinase 2 / p125FAK / pp125FAK


Mass: 75476.445 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Gallus gallus (chicken) / Gene: PTK2, FAK, FAK1 / Production host: Homo sapiens (human)
References: UniProt: Q00944, non-specific protein-tyrosine kinase

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: 2D ARRAY / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Focal adhesion kinase / Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.15 MDa / Experimental value: NO
Source (natural)Organism: Gallus gallus (chicken)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 5.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company /
Model: Tecnai Polara / Image courtesy: FEI Company
EM imaging

Accelerating voltage: 300 kV / Electron source: FIELD EMISSION GUN / Illumination mode: FLOOD BEAM / Mode: BRIGHT FIELD / Specimen-ID: 1

IDC2 aperture diameter (µm)ModelCs (mm)
1100FEI TITAN KRIOS2.7
2FEI POLARA 3002.26
Image recording
IDImaging-IDElectron dose (e/Å2)Detector modeFilm or detector model
1140COUNTINGGATAN K2 SUMMIT (4k x 4k)
2240COUNTINGGATAN K2 SUMMIT (4k x 4k)

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Processing

EM software
IDNameCategoryImaging-ID
2SerialEMimage acquisition1
7iMODFITmodel fitting
12cryoSPARC3D reconstruction
13PHENIXmodel refinement
15SerialEMimage acquisition2
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionResolution: 6.32 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 106785 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Atomic model building

3D fitting-ID: 1 / Pdb chain-ID: A / Source name: PDB / Type: experimental model

IDPDB-IDAccession codeInitial refinement model-IDPdb chain residue range
12AEH

2aeh

2AEH133-363
21MP8

1mp8

1MP82414-686

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