LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade.
A549 Cells
Adaptor Proteins, Signal Transducing
/ genetics
Binding Sites
/ genetics
Cell Line
Cilia
/ metabolism
HEK293 Cells
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
/ genetics
Myosin Heavy Chains
/ genetics
Myosin Type V
/ genetics
Phosphorylation
Protein Binding
/ genetics
rab GTP-Binding Proteins
/ metabolism
Journal
Life science alliance
ISSN: 2575-1077
Titre abrégé: Life Sci Alliance
Pays: United States
ID NLM: 101728869
Informations de publication
Date de publication:
05 2021
05 2021
Historique:
received:
08
02
2021
revised:
26
02
2021
accepted:
01
03
2021
entrez:
17
3
2021
pubmed:
18
3
2021
medline:
13
10
2021
Statut:
epublish
Résumé
Activating mutations in LRRK2 kinase causes Parkinson's disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with strong preference to LRRK2-phosphorylated Rab8A and Rab10. RILPL2 is a binding partner of the motor protein and Rab effector, Myosin Va. We show here that the globular tail domain of Myosin Va also contains a high affinity binding site for LRRK2-phosphorylated Rab10. In the presence of pathogenic LRRK2, RILPL2 and MyoVa relocalize to the peri-centriolar region in a phosphoRab10-dependent manner. PhosphoRab10 retains Myosin Va over pericentriolar membranes as determined by fluorescence loss in photobleaching microscopy. Without pathogenic LRRK2, RILPL2 is not essential for ciliogenesis but RILPL2 over-expression blocks ciliogenesis in RPE cells independent of tau tubulin kinase recruitment to the mother centriole. These experiments show that LRRK2 generated-phosphoRab10 dramatically redistributes a significant fraction of Myosin Va and RILPL2 to the mother centriole in a manner that likely interferes with Myosin Va's role in ciliogenesis.
Identifiants
pubmed: 33727250
pii: 4/5/e202101050
doi: 10.26508/lsa.202101050
pmc: PMC7994366
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
MYO5A protein, human
148971-15-7
LRRK2 protein, human
EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
Myosin Type V
EC 3.6.1.-
Rab10 protein, human
EC 3.6.1.-
RAB8A protein, human
EC 3.6.1.-.
Myosin Heavy Chains
EC 3.6.4.1
rab GTP-Binding Proteins
EC 3.6.5.2
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 : NIDDK NIH HHS
ID : R01 DK037332
Pays : United States
Organisme : NIDDK NIH HHS
ID : R37 DK037332
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK037332
Pays : United States
Informations de copyright
© 2021 Dhekne et al.
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