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Related Experiment Videos

Structural insights into Ras regulation by SIN1.

Yuyuan Zheng1,2,3, Lei Ding1,2, Xianhui Meng3

  • 1School of Public Health, Zhejiang University School of Medicine, Hangzhou, 310058, China.

Proceedings of the National Academy of Sciences of the United States of America
|May 6, 2022
PubMed
Summary

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This summary is machine-generated.

The study reveals how SIN1 (stress-activated protein kinase-interacting protein 1) binds to Ras proteins, impacting cell signaling pathways. This interaction influences cell growth and survival by modulating mTORC2 and Ras-ERK pathways.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Structural Biology

Background:

  • SIN1 is a key component of mTORC2, known to interact with Ras GTPases via its Ras-binding domain (RBD).
  • The physical association between Ras and SIN1/mTORC2 may influence both mTORC2 activity and the Ras-ERK pathway.
  • Understanding this interaction is crucial for deciphering crosstalk between growth factor-stimulated pathways.

Purpose of the Study:

  • To determine the high-resolution structures of HRas/KRas-SIN1 RBD complexes.
  • To elucidate the precise molecular mechanism of Ras-SIN1 interaction.
  • To investigate the functional consequences of Ras-SIN1 association on cellular signaling.

Main Methods:

  • High-resolution structural determination of HRas/KRas-SIN1 RBD complexes.
Keywords:
PI3KRasSIN1insulinmTORC2

Related Experiment Videos

  • Site-directed mutagenesis of critical interface residues.
  • Experiments in SIN1 knockout cells.
  • Competition fluorescence resonance energy transfer (FRET) assays.
  • Structural comparisons with other Ras-binding proteins.

    • Main Results:

    • Detailed interaction interfaces between Ras and SIN1 RBD were revealed by structural analysis.
    • Mutations at the interface disrupted Ras-SIN1 binding.
    • Ras-SIN1 association was shown to promote SGK1 activity and inhibit insulin-induced ERK activation in SIN1 knockout cells.
    • HRas-SIN1 RBD binding affinity was quantified relative to HRas-Raf1 RBD and HRas-PI3K RBD.
    • SIN1 isoforms lacking the PH domain exhibited stronger Ras binding, suggesting an inhibitory role for the PH domain.

    Conclusions:

    • The study provides atomic-level insights into Ras-SIN1 interaction and its functional implications.
    • Ras-SIN1 association plays a role in modulating SGK1 activity and ERK pathway signaling.
    • The binding affinity and regulation by SIN1 isoforms offer explanations for differential pathway activation.
    • A novel Ras dimerization interface was identified, potentially involved in Ras oligomerization.
    • These findings advance the understanding of signal integration and crosstalk in growth factor signaling pathways.