High-affinity Interactions of the nSH3/cSH3 Domains of Grb2 with the C-terminal Proline-rich Domain of SOS1.

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ID: 87530
2020
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Abstract
Grb2 is an adaptor protein that recruits Ras-specific guanine nucleotide exchange factor, Son of Sevenless 1 (SOS1), to the plasma membrane. SOS1 exchanges GDP by GTP, activating Ras. Grb2 consists of an SH2 domain flanked by N- and C-terminal SH3 domains (nSH3/cSH3). Grb2 nSH3/cSH3 domains have strong binding affinity for SOS1 proline-rich (PR) domain that mediates the Grb2-SOS1 interaction. The nSH3/cSH3 domains have distinct preferred binding motifs: PxxPxR for nSH3 and PxxxRxxKP for cSH3 (x represents any natural amino acid). Several nSH3-binding motifs have been identified in the SOS1 PR domain but none specific for cSH3 binding. Even though both nSH3 and cSH3 exhibit the strongest binding to the SOS1 peptide PVPPPVPPRRRP, this mutually-exclusive binding combined with other potential nSH3/cSH3 binding regions in SOS1 make understanding the Grb2-SOS1 interaction challenging. To identify the SOS1-cSH3 binding sites, we selected seven potential binding segments in SOS1. The synthesized peptides were tested for their binding to nSH3/cSH3. Our NMR data reveal that PKLPPKTYKREH peptide has strong binding affinity for cSH3, but very weak for nSH3. The binding specificity suggests that the most likely Grb2-SOS1 binding mode is through nSH3-PVPPPVPPRRRP and cSH3-PKLPPKTYKREH interactions, which is supported by replica-exchange simulations for the Grb2-SOS1 complex models. We propose that nSH3/cSH3 binding peptides, which effectively interrupt Grb2-SOS1 association, can serve as tumor suppressors. The Grb2-SOS1 mechanism outlined here offers new venues for future therapeutic strategies for upstream mutations in cancer, such as in EGFR.
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liao2020highaffinityjournal Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Liao, Tsung-Jen;Jang, Hyunbum;Nussinov, Ruth;Fushman, David;
Journal Journal of the American Chemical Society
Year 2020
DOI
10.1021/jacs.9b10710
URL
Keywords
cost-effectiveness pneumonia pharmacoeconomics vaccine effectiveness pcv13 ppsv23 decision analytics invasive pneumococcal diseases pneumococcal infection

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