SOS1 interacts with Grb2 through regions that induce closed nSH3 conformations

Area of Science:

• Molecular Biology
• Cell Signaling
• Biophysics

Background:

• Grb2 is a key adaptor protein linking epidermal growth factor receptor (EGFR) to Son of sevenless 1 (SOS1).
• SOS1 is a Ras-specific guanine nucleotide exchange factor (RasGEF) crucial for Ras signaling.
• Grb2 possesses N-terminal SH3 (nSH3), SH2, and C-terminal SH3 (cSH3) domains, with its conformation regulated by SOS1's proline-rich (PR) domain.

Purpose of the Study:

• To elucidate how binding of SOS1's PR domain to Grb2's SH3 domains influences Grb2 conformation.
• To identify specific binding sites on SOS1's PR domain that interact with Grb2's cSH3 domain.
• To provide insights for designing novel inhibitors of the Grb2-SOS1 interaction.

Main Methods:

• Extensive molecular dynamics (MD) simulations totaling 248 microseconds across 620 trajectories.
• Construction of an effective free energy landscape to validate binding sites.
• Analysis of Grb2-SOS1 peptide complex models.

Main Results:

• Strong peptide binders from SOS1's PR domain induce a closed conformation of Grb2's nSH3 domain by attracting the flexible n-Src loop.
• The conformation of Grb2's cSH3 domain remains unchanged upon peptide binding.
• Validated specific cSH3 binding regions within the SOS1 PR domain.

Conclusions:

• The study reveals a mechanism by which SOS1 PR segments modulate Grb2 conformation, specifically affecting the nSH3 domain.
• These findings offer a structural basis for understanding Grb2-SOS1 complex formation.
• The uncovered conformational details can guide the development of therapeutic polypeptides targeting Grb2-SOS1 interaction to inhibit Ras signaling.