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- PDB-8dyu: Structure of human cytoplasmic dynein-1 bound to two Lis1 proteins -

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Basic information

Entry
Database: PDB / ID: 8dyu
TitleStructure of human cytoplasmic dynein-1 bound to two Lis1 proteins
Components
  • Cytoplasmic dynein 1 heavy chain 1
  • Platelet-activating factor acetylhydrolase IB subunit beta
KeywordsMOTOR PROTEIN / dynein / transport
Function / homology
Function and homology information


microtubule cytoskeleton organization involved in establishment of planar polarity / establishment of planar polarity of embryonic epithelium / 1-alkyl-2-acetylglycerophosphocholine esterase complex / cerebral cortex neuron differentiation / corpus callosum morphogenesis / establishment of centrosome localization / platelet activating factor metabolic process / acrosome assembly / platelet activating factor catabolic process / layer formation in cerebral cortex ...microtubule cytoskeleton organization involved in establishment of planar polarity / establishment of planar polarity of embryonic epithelium / 1-alkyl-2-acetylglycerophosphocholine esterase complex / cerebral cortex neuron differentiation / corpus callosum morphogenesis / establishment of centrosome localization / platelet activating factor metabolic process / acrosome assembly / platelet activating factor catabolic process / layer formation in cerebral cortex / central region of growth cone / auditory receptor cell development / microtubule sliding / positive regulation of embryonic development / microtubule organizing center organization / astral microtubule / cortical microtubule organization / reelin-mediated signaling pathway / brain morphogenesis / positive regulation of dendritic spine morphogenesis / positive regulation of intracellular transport / positive regulation of spindle assembly / regulation of metaphase plate congression / stem cell division / establishment of spindle localization / stereocilium / neuromuscular process controlling balance / microtubule plus-end binding / positive regulation of mitotic cell cycle spindle assembly checkpoint / motile cilium / vesicle transport along microtubule / germ cell development / retrograde axonal transport / COPI-independent Golgi-to-ER retrograde traffic / minus-end-directed microtubule motor activity / P-body assembly / microtubule associated complex / dynein light intermediate chain binding / cytoplasmic dynein complex / nuclear migration / kinesin complex / neuroblast proliferation / establishment of mitotic spindle orientation / dynein intermediate chain binding / cell leading edge / transmission of nerve impulse / dynein complex binding / male germ cell nucleus / cochlea development / dynactin binding / positive regulation of axon extension / adult locomotory behavior / microtubule-based process / COPI-mediated anterograde transport / cytoplasmic microtubule / positive regulation of mitotic cell cycle / phospholipase binding / cytoplasmic microtubule organization / axon cytoplasm / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / Recruitment of mitotic centrosome proteins and complexes / MHC class II antigen presentation / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / AURKA Activation by TPX2 / hippocampus development / Resolution of Sister Chromatid Cohesion / stress granule assembly / mitotic spindle organization / regulation of mitotic spindle organization / regulation of microtubule cytoskeleton organization / negative regulation of neuron projection development / filopodium / neuron migration / cerebral cortex development / phosphoprotein binding / RHO GTPases Activate Formins / microtubule cytoskeleton organization / modulation of chemical synaptic transmission / Schaffer collateral - CA1 synapse / kinetochore / HCMV Early Events / Aggrephagy / azurophil granule lumen / Separation of Sister Chromatids / Regulation of PLK1 Activity at G2/M Transition / nuclear envelope / heparin binding / positive regulation of cold-induced thermogenesis / nuclear membrane / actin cytoskeleton organization / chemical synaptic transmission / cell cortex / microtubule binding / microtubule
Similarity search - Function
: / : / PAC1 LisH domain / Dynein regulator LIS1 / LIS1, N-terminal / Lissencephaly type-1-like homology motif / Dynein heavy chain, AAA 5 extension domain / Dynein heavy chain AAA lid domain / Dynein heavy chain, C-terminal domain / Dynein heavy chain, C-terminal domain, barrel region ...: / : / PAC1 LisH domain / Dynein regulator LIS1 / LIS1, N-terminal / Lissencephaly type-1-like homology motif / Dynein heavy chain, AAA 5 extension domain / Dynein heavy chain AAA lid domain / Dynein heavy chain, C-terminal domain / Dynein heavy chain, C-terminal domain, barrel region / Dynein heavy chain C-terminal domain / LIS1 homology (LisH) motif profile. / LIS1 homology motif / : / Dynein heavy chain, ATPase lid domain / Dynein heavy chain, tail / Dynein heavy chain, N-terminal region 1 / P-loop containing dynein motor region / Dynein heavy chain region D6 P-loop domain / Dynein heavy chain, linker / Dynein heavy chain, AAA module D4 / Dynein heavy chain, coiled coil stalk / Dynein heavy chain / Dynein heavy chain, hydrolytic ATP-binding dynein motor region / Dynein heavy chain, ATP-binding dynein motor region / Dynein heavy chain AAA lid domain / Dynein heavy chain AAA lid domain superfamily / Dynein heavy chain, domain 2, N-terminal / Dynein heavy chain, linker, subdomain 3 / Dynein heavy chain, AAA1 domain, small subdomain / Dynein heavy chain region D6 P-loop domain / Dynein heavy chain, N-terminal region 2 / Hydrolytic ATP binding site of dynein motor region / Microtubule-binding stalk of dynein motor / P-loop containing dynein motor region D4 / ATP-binding dynein motor region / Dynein heavy chain AAA lid domain / WD domain, G-beta repeat / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE-5'-DIPHOSPHATE / ADENOSINE-5'-TRIPHOSPHATE / Platelet-activating factor acetylhydrolase IB subunit beta / Cytoplasmic dynein 1 heavy chain 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4 Å
AuthorsReimer, J.M. / DeSantis, M. / Reck-Peterson, S.L. / Leschziner, A.E.
Funding support United States, 2items
OrganizationGrant numberCountry
Damon Runyon Cancer Research FoundationDRG-2370-19 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01 GM107214 United States
Citation
Journal: Elife / Year: 2023
Title: Structures of human dynein in complex with the lissencephaly 1 protein, LIS1.
Authors: Janice M Reimer / Morgan E DeSantis / Samara L Reck-Peterson / Andres E Leschziner /
Abstract: The lissencephaly 1 protein, LIS1, is mutated in type-1 lissencephaly and is a key regulator of cytoplasmic dynein-1. At a molecular level, current models propose that LIS1 activates dynein by ...The lissencephaly 1 protein, LIS1, is mutated in type-1 lissencephaly and is a key regulator of cytoplasmic dynein-1. At a molecular level, current models propose that LIS1 activates dynein by relieving its autoinhibited form. Previously we reported a 3.1 Å structure of yeast dynein bound to Pac1, the yeast homologue of LIS1, which revealed the details of their interactions (Gillies et al., 2022). Based on this structure, we made mutations that disrupted these interactions and showed that they were required for dynein's function in vivo in yeast. We also used our yeast dynein-Pac1 structure to design mutations in human dynein to probe the role of LIS1 in promoting the assembly of active dynein complexes. These mutations had relatively mild effects on dynein activation, suggesting that there may be differences in how dynein and Pac1/LIS1 interact between yeast and humans. Here, we report cryo-EM structures of human dynein-LIS1 complexes. Our new structures reveal the differences between the yeast and human systems, provide a blueprint to disrupt the human dynein-LIS1 interactions more accurately, and map type-1 lissencephaly disease mutations, as well as mutations in dynein linked to malformations of cortical development/intellectual disability, in the context of the dynein-LIS1 complex.
#1: Journal: Elife / Year: 2022
Title: Structural basis for cytoplasmic dynein-1 regulation by Lis1.
Authors: Gillies, J.P. / Reimer, J.M. / Karasmanis, E.P. / Lahiri, I. / Htet, Z.M. / Leschziner, A.E. / Reck-Peterson, S.L.
History
DepositionAug 5, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 1, 2023Provider: repository / Type: Initial release
Revision 1.0Feb 1, 2023Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 1, 2023Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
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Revision 1.0Feb 1, 2023Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
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Revision 1.0Feb 1, 2023Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Feb 1, 2023Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 1, 2023Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.1Jun 12, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Revision 1.2May 21, 2025Group: Data collection / Structure summary / Category: em_admin / em_software / pdbx_entry_details
Item: _em_admin.last_update / _em_software.name / _pdbx_entry_details.has_protein_modification
Revision 1.1May 21, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cytoplasmic dynein 1 heavy chain 1
B: Platelet-activating factor acetylhydrolase IB subunit beta
C: Platelet-activating factor acetylhydrolase IB subunit beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)476,1887
Polymers474,3993
Non-polymers1,7894
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Cytoplasmic dynein 1 heavy chain 1


Mass: 380953.594 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q14204
#2: Protein Platelet-activating factor acetylhydrolase IB subunit beta / Lissencephaly-1 protein / LIS-1 / PAF acetylhydrolase 45 kDa subunit / PAF-AH 45 kDa subunit / PAF- ...Lissencephaly-1 protein / LIS-1 / PAF acetylhydrolase 45 kDa subunit / PAF-AH 45 kDa subunit / PAF-AH alpha / PAFAH alpha


Mass: 46722.918 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PAFAH1B1, LIS1, MDCR, MDS, PAFAHA / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P43034
#3: Chemical ChemComp-ADP / ADENOSINE-5'-DIPHOSPHATE


Mass: 427.201 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H15N5O10P2 / Comment: ADP, energy-carrying molecule*YM
#4: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Comment: ATP, energy-carrying molecule*YM
Has ligand of interestN
Has protein modificationN

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Experimental details

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Experiment

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

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Sample preparation

ComponentName: Human cytoplasmic dynein-1 bound to two Lis1 WD40 domains.
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
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: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.1_4122: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 37288 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00425184
ELECTRON MICROSCOPYf_angle_d0.78334257
ELECTRON MICROSCOPYf_dihedral_angle_d6.6373427
ELECTRON MICROSCOPYf_chiral_restr0.0453924
ELECTRON MICROSCOPYf_plane_restr0.0064363

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