Conformation and dynamics of the kinase domain drive subcellular location and activation of LRRK2.
Gaussian accelerated molecular dynamics
Parkinson’s disease
hydrogen-deuterium exchange mass spectrometry (HDX-MS)
kinase regulation
leucine-rich repeat kinase 2 (LRRK2)
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
08 06 2021
08 06 2021
Historique:
entrez:
5
6
2021
pubmed:
6
6
2021
medline:
1
12
2021
Statut:
ppublish
Résumé
To explore how pathogenic mutations of the multidomain leucine-rich repeat kinase 2 (LRRK2) hijack its finely tuned activation process and drive Parkinson's disease (PD), we used a multitiered approach. Most mutations mimic Rab-mediated activation by "unleashing" kinase activity, and many, like the kinase inhibitor MLi-2, trap LRRK2 onto microtubules. Here we mimic activation by simply deleting the inhibitory N-terminal domains and then characterize conformational changes induced by MLi-2 and PD mutations. After confirming that LRRK2
Identifiants
pubmed: 34088839
pii: 2100844118
doi: 10.1073/pnas.2100844118
pmc: PMC8201809
pii:
doi:
Substances chimiques
LRRK2 protein, human
EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
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
Subventions
Organisme : NIGMS NIH HHS
ID : P41 GM103412
Pays : United States
Organisme : NIGMS NIH HHS
ID : R24 GM137200
Pays : United States
Organisme : NIH HHS
ID : S10 OD016234
Pays : United States
Organisme : NINDS NIH HHS
ID : U24 NS120055
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009523
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM086197
Pays : United States
Informations de copyright
Copyright © 2021 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
The authors declare no competing interest.
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