Lis1 relieves cytoplasmic dynein-1 autoinhibition by acting as a molecular wedge.
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
received:
27
10
2022
accepted:
14
07
2023
medline:
14
9
2023
pubmed:
25
8
2023
entrez:
24
8
2023
Statut:
ppublish
Résumé
Cytoplasmic dynein-1 transports intracellular cargo towards microtubule minus ends. Dynein is autoinhibited and undergoes conformational changes to form an active complex that consists of one or two dynein dimers, the dynactin complex, and activating adapter(s). The Lissencephaly 1 gene, LIS1, is genetically linked to the dynein pathway from fungi to mammals and is mutated in people with the neurodevelopmental disease lissencephaly. Lis1 is required for active dynein complexes to form, but how it enables this is unclear. Here, we present a structure of two yeast dynein motor domains with two Lis1 dimers wedged in-between. The contact sites between dynein and Lis1 in this structure, termed 'Chi,' are required for Lis1's regulation of dynein in Saccharomyces cerevisiae in vivo and the formation of active human dynein-dynactin-activating adapter complexes in vitro. We propose that this structure represents an intermediate in dynein's activation pathway, revealing how Lis1 relieves dynein's autoinhibited state.
Identifiants
pubmed: 37620585
doi: 10.1038/s41594-023-01069-6
pii: 10.1038/s41594-023-01069-6
pmc: PMC10497415
doi:
Substances chimiques
Cytoplasmic Dyneins
EC 3.6.4.2
Dyneins
EC 3.6.4.2
Dynactin Complex
0
Oligonucleotides
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1357-1364Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM107214
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM141825
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM145296
Pays : United States
Informations de copyright
© 2023. The Author(s).
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