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

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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


corpus callosum morphogenesis / establishment of planar polarity of embryonic epithelium / microtubule cytoskeleton organization involved in establishment of planar polarity / ameboidal-type cell migration / interneuron migration / 1-alkyl-2-acetylglycerophosphocholine esterase complex / maintenance of centrosome location / microtubule sliding / platelet activating factor metabolic process / radial glia-guided pyramidal neuron migration ...corpus callosum morphogenesis / establishment of planar polarity of embryonic epithelium / microtubule cytoskeleton organization involved in establishment of planar polarity / ameboidal-type cell migration / interneuron migration / 1-alkyl-2-acetylglycerophosphocholine esterase complex / maintenance of centrosome location / microtubule sliding / platelet activating factor metabolic process / radial glia-guided pyramidal neuron migration / cerebral cortex neuron differentiation / microtubule organizing center organization / positive regulation of intracellular transport / central region of growth cone / acrosome assembly / positive regulation of embryonic development / reelin-mediated signaling pathway / regulation of metaphase plate congression / establishment of centrosome localization / positive regulation of cytokine-mediated signaling pathway / cortical microtubule organization / establishment of spindle localization / astral microtubule / axonemal dynein complex / positive regulation of spindle assembly / nuclear membrane disassembly / layer formation in cerebral cortex / auditory receptor cell development / vesicle transport along microtubule / positive regulation of dendritic spine morphogenesis / stem cell division / stereocilium / myeloid leukocyte migration / dynein complex / P-body assembly / COPI-independent Golgi-to-ER retrograde traffic / negative regulation of JNK cascade / minus-end-directed microtubule motor activity / dynein light intermediate chain binding / microtubule plus-end binding / cytoplasmic dynein complex / brain morphogenesis / motile cilium / retrograde axonal transport / nuclear migration / microtubule associated complex / osteoclast development / kinesin complex / dynein intermediate chain binding / dynein complex binding / cochlea development / cell leading edge / transmission of nerve impulse / germ cell development / cytoplasmic microtubule / establishment of mitotic spindle orientation / dynactin binding / microtubule-based process / phospholipase binding / neuromuscular process controlling balance / protein secretion / neuroblast proliferation / positive regulation of axon extension / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / COPI-mediated anterograde transport / regulation of microtubule cytoskeleton organization / lipid catabolic process / stress granule assembly / Mitotic Prometaphase / cytoplasmic microtubule organization / EML4 and NUDC in mitotic spindle formation / regulation of mitotic spindle organization / JNK cascade / axon cytoplasm / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of mitotic centrosome proteins and complexes / Resolution of Sister Chromatid Cohesion / 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 / MHC class II antigen presentation / positive regulation of mitotic cell cycle / AURKA Activation by TPX2 / adult locomotory behavior / mitotic spindle organization / filopodium / RHO GTPases Activate Formins / hippocampus development / phosphoprotein binding / neuron migration / Schaffer collateral - CA1 synapse / modulation of chemical synaptic transmission / cerebral cortex development / kinetochore / Aggrephagy / microtubule cytoskeleton organization / HCMV Early Events / Separation of Sister Chromatids / Regulation of PLK1 Activity at G2/M Transition
Similarity search - Function
Dynein regulator LIS1 / LIS1, N-terminal / LisH / 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 / Lissencephaly type-1-like homology motif / P-loop containing dynein motor region ...Dynein regulator LIS1 / LIS1, N-terminal / LisH / 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 / Lissencephaly type-1-like homology motif / P-loop containing dynein motor region / Dynein heavy chain, tail / Dynein heavy chain, N-terminal region 1 / Dynein heavy chain / 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, 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 / LIS1 homology (LisH) motif profile. / LIS1 homology motif / 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. / WD domain, G-beta repeat / 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 1.1Jun 12, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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Structure visualization

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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

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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
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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