Dissecting the effects of GTPase and kinase domain mutations on LRRK2 endosomal localization and activity.
Cell Rep
; 42(5): 112447, 2023 05 30.
Article
em En
| MEDLINE
| ID: mdl-37141099
ABSTRACT
Parkinson's disease-causing leucine-rich repeat kinase 2 (LRRK2) mutations lead to varying degrees of Rab GTPase hyperphosphorylation. Puzzlingly, LRRK2 GTPase-inactivating mutations-which do not affect intrinsic kinase activity-lead to higher levels of cellular Rab phosphorylation than kinase-activating mutations. Here, we investigate whether mutation-dependent differences in LRRK2 cellular localization could explain this discrepancy. We discover that blocking endosomal maturation leads to the rapid formation of mutant LRRK2+ endosomes on which LRRK2 phosphorylates substrate Rabs. LRRK2+ endosomes are maintained through positive feedback, which mutually reinforces membrane localization of LRRK2 and phosphorylated Rab substrates. Furthermore, across a panel of mutants, cells expressing GTPase-inactivating mutants form strikingly more LRRK2+ endosomes than cells expressing kinase-activating mutants, resulting in higher total cellular levels of phosphorylated Rabs. Our study suggests that the increased probability that LRRK2 GTPase-inactivating mutants are retained on intracellular membranes compared to kinase-activating mutants leads to higher substrate phosphorylation.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Serina-Treonina Quinases
/
Proteínas rab de Ligação ao GTP
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article