New mechanistic insights into the RAS-SIN1 interaction at the membrane.
MAPKAP1
PH domain
RAS
RAS family
SIN1
mTORC2
membrane binding
ras binding domain
Journal
Frontiers in cell and developmental biology
ISSN: 2296-634X
Titre abrégé: Front Cell Dev Biol
Pays: Switzerland
ID NLM: 101630250
Informations de publication
Date de publication:
2022
2022
Historique:
received:
06
07
2022
accepted:
20
09
2022
entrez:
24
10
2022
pubmed:
25
10
2022
medline:
25
10
2022
Statut:
epublish
Résumé
Stress-activated MAP kinase-interacting protein 1 (SIN1) is a central member of the mTORC2 complex that contains an N-terminal domain (NTD), a conserved region in the middle (CRIM), a RAS-binding domain (RBD), and a pleckstrin homology domain. Recent studies provided valuable structural and functional insights into the interactions of SIN1 and the RAS-binding domain of RAS proteins. However, the mechanism for a reciprocal interaction of the RBD-PH tandem with RAS proteins and the membrane as an upstream event to spatiotemporal mTORC2 regulation is not clear. The biochemical assays in this study led to the following results: 1) all classical RAS paralogs, including HRAS, KRAS4A, KRAS4B, and NRAS, can bind to SIN1-RBD in biophysical and SIN1 full length (FL) in cell biology experiments; 2) the SIN1-PH domain modulates interactions with various types of membrane phosphoinositides and constantly maintains a pool of SIN1 at the membrane; and 3) a KRAS4A-dependent decrease in membrane binding of the SIN1-RBD-PH tandem was observed, suggesting for the first time a mechanistic influence of KRAS4A on SIN1 membrane association. Our study strengthens the current mechanistic understanding of SIN1-RAS interaction and suggests membrane interaction as a key event in the control of mTORC2-dependent and mTORC2-independent SIN1 function.
Identifiants
pubmed: 36274845
doi: 10.3389/fcell.2022.987754
pii: 987754
pmc: PMC9583166
doi:
Types de publication
Journal Article
Langues
eng
Pagination
987754Informations de copyright
Copyright © 2022 Pudewell, Lissy, Nakhaeizadeh, Mosaddeghzadeh, Nakhaei-Rad, Dvorsky and Ahmadian.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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