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Structure paper

TitleMultiple steps of dynein activation by Lis1 visualized by cryo-EM.
Journal, issue, pagesNat Struct Mol Biol, Year 2025
Publish dateMay 23, 2025
AuthorsAgnieszka A Kendrick / Kendrick H V Nguyen / Wen Ma / Eva P Karasmanis / Rommie E Amaro / Samara L Reck-Peterson / Andres E Leschziner /
PubMed AbstractCytoplasmic dynein-1 (dynein) is an essential molecular motor controlled in part by autoinhibition. Lis1, a key dynein regulator mutated in the neurodevelopmental disease lissencephaly, plays a role ...Cytoplasmic dynein-1 (dynein) is an essential molecular motor controlled in part by autoinhibition. Lis1, a key dynein regulator mutated in the neurodevelopmental disease lissencephaly, plays a role in dynein activation. We recently identified a structure of partially autoinhibited dynein bound to Lis1, which suggests an intermediate state in dynein's activation pathway. However, other structural information is needed to fully understand how Lis1 activates dynein. Here, we used cryo-EM and yeast dynein and Lis1 incubated with ATP at different time points to reveal conformations that we propose represent additional intermediate states in dynein's activation pathway. We solved 16 high-resolution structures, including 7 distinct dynein and dynein-Lis1 structures from the same sample. Our data support a model in which Lis1 relieves dynein autoinhibition by increasing its basal ATP hydrolysis rate and promoting conformations compatible with complex assembly and motility. Together, this analysis advances our understanding of dynein activation and the contribution of Lis1 to this process.
External linksNat Struct Mol Biol / PubMed:40410592
MethodsEM (single particle)
Resolution2.8 - 4.1 Å
Structure data

EMDB-46897, PDB-9di3:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 4.1 Å

EMDB-46919, PDB-9diu:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 4.1 Å

EMDB-46935, PDB-9dj7:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-46938, PDB-9dju:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 4.0 Å

EMDB-46940, PDB-9djy:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-46941, PDB-9djz:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-46942, PDB-9dk0:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-46953, PDB-9dkd:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-46954, PDB-9dke:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-46958, PDB-9dkh:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-46959, PDB-9dkj:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-46962, PDB-9dkm:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-46972, PDB-9dkx:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-46974, PDB-9dld:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-46975, PDB-9dle:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-47019, PDB-9dmw:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-47026, PDB-9dn5:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-47032, PDB-9dn7:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.25 Å

EMDB-47033, PDB-9dnb:
CryoEM structures of yeast cytoplasmic dynein in the presence of ATP and Lis1.
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

Source
  • saccharomyces cerevisiae (brewer's yeast)
KeywordsMOTOR PROTEIN / Enzyme / AAA protein / AAA+ protein

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