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Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Biophysics

Background:

  • Mitogen-activated protein kinase (MAPK) signaling is crucial for cellular processes.
  • RAF proteins bind active RAS at the plasma membrane via RAS-binding (RBD) and cysteine-rich domains (CRD).
  • RAS membrane orientation is hypothesized to be critical for RAS-RBD-CRD complex formation and signaling.

Purpose of the Study:

  • To investigate the relationship between RAS membrane orientation and protein dynamics within the RAS-RBD-CRD complex.
  • To explore how membrane anchoring affects the structure and dynamics of the KRAS4b-RAF-1 complex.

Main Methods:

  • Multiscale coarse-grained and all-atom molecular dynamics (MD) simulations.
  • Simulations of KRAS4b bound to RAF-1 RBD and CRD in solution and anchored to a model plasma membrane.

Main Results:

  • Solution simulations revealed dynamic KRAS4b-CRD conformations with a flexible CRD binding interface.
  • Membrane-anchored simulations showed restricted CRD mobility, fewer KRAS4b-CRD conformations, and specific membrane-oriented configurations.
  • A membrane-specific configuration emerged with CRD loops inserted into the membrane and KRAS4b helices exposed, stabilized by novel contacts.

Conclusions:

  • The plasma membrane modulates RAS/RAF complex structure and dynamics through interplay with the CRD.
  • Membrane anchoring influences KRAS4b-RAF-1 complex conformation, potentially impacting MAPK signaling activation.
  • Observed membrane-specific configurations align with NMR data and suggest a role for membrane interactions in signal transduction.