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New mechanistic insights into the RAS-SIN1 interaction at the membrane.

ABSTRACT: 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.

SUBMITTER: Pudewell S

PROVIDER: S-EPMC9583166 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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New mechanistic insights into the RAS-SIN1 interaction at the membrane.

Pudewell Silke S Lissy Jana J Nakhaeizadeh Hossein H Mosaddeghzadeh Niloufar N Nakhaei-Rad Saeideh S Dvorsky Radovan R Ahmadian Mohammad R MR

Frontiers in cell and developmental biology 20221006

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 ...[more]

PMID: 36274845

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Dataset Information

New mechanistic insights into the RAS-SIN1 interaction at the membrane.

Publications

New mechanistic insights into the RAS-SIN1 interaction at the membrane.

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