Correction: Crystal structures of p120RasGAP N-terminal SH2 domain in its apo form and in complex with a p190RhoGAP phosphotyrosine peptide

SHP2–EGFR States in Dephosphorylation Can Inform Selective SHP2 Inhibitors, Dampening RasGAP Action

“…Here, we explored how SHP2 interferes with the function of a RasGAP, RASA1 (p120RasGAP), to regulate the EGFR-dependent Ras/MAPK signaling. Our observations support and provide mechanistic details for a wide range of experimental findings. ,,,,,− Our simulations of the complexes of different EGFR-derived pY-peptides with the nSH2 and cSH2 domains of RASA1 and with the PTP domain of SHP2 support that pY992 of EGFR is the negative regulatory phosphorylation site exactly recognized by RASA1 and dephosphorylated by SHP2. , The specificity and affinity of the binding, as well as the precise residue–residue interaction for these complexes collectively imply that the nSH2 domain of RASA1 serves as the primary binder to EGFR in RASA1–EGFR recognition. This is mainly due to the synergistic effects of two factors: (i) the two positively charged residues in the BC-loop of the nSH2 domain of RASA1 and (ii) the presence of two negatively charged residues at the −2 and −1 positions N-terminal to pY992 of EGFR, which provide additional interactions and significantly promote recognition.…”

“…These findings align with the experimental observations that two p190RhoGAP-derived pY-peptides (EEENIpYSVPHDS and DpYAEPMDA) with the pYxxP motif bind specifically to the nSH2 and cSH2 domains of RASA1, respectively (Figure S3). ,, Although the nSH2–pY-P5 system exhibited binding specificity in our simulation, we cannot conclusively ascertain that pYxxxP with proline at the +4 position is the binding motif for this nSH2. This uncertainty stems from the observation that pY-P3, sharing the same motif (pYSSDP), failed to exhibit specific binding to this domain.…”

“…During the nSH2–pY-P2 binding, D990 and E991 in pY-P2 orient toward the BC-loop of nSH2, forming hydrophilic interactions (hydrogen bond and salt bridge) with R212 and R211 in the BC-loop of nSH2, respectively (Figure c and Table S6). In addition to the conserved interactions of pY992 in pY-P2 with the residues within the pY-binding pocket of nSH2 (R188–pY992, R207–pY992, S209–pY992, and R231-pY992), , the coexistence of D990/E991 in the peptide and R211/R212 in nSH2 strongly enhances the nSH2–pY-P2 interaction, contributing a total interaction energy of ∼−389.9 kcal/mol (Figure d and Table S7). Unlike D990 and E991 in pY-P2, P1099 and H1100 in pY-P6 in the nSH2–pY-P6 system are oriented opposite to nSH2, and R212 in its BC-loop is directed away from the pY-binding pocket (Figure c).…”

“…Crystal structures of different pY-peptides bound to the nSH2 and cSH2 domains of RASA1 show a preference of the two SH2 domains for the pYxxP motif (where x represents any natural amino acid) with a proline residue at the +3 position C-terminal to pY (Figure S3). 31,37,38 In EGFR, two sites, pY992 (pYLIP) and pY1101 (pYQDP), match this motif. The RASA1-binding site also raises questions such as how SHP2 influences RASA1's regulation of EGFR-dependent Ras signaling, and how RASA1 recognizes EGFR's pY site in recruitment.…”

SH3 domain regulation of RhoGAP activity: Crosstalk between p120RasGAP and DLC1 RhoGAP

“…The roles and divergence of Src homology domains away from their canonical features continue to be identified 34 – 36 , including the recent discovery of a unique mode of phosphotyrosine binding by one of the SH2 domains of p120RasGAP 37 . We, therefore, hypothesized that the interaction of the p120RasGAP SH3 domain with the DLC1 RhoGAP domain may represent an atypical mode of SH3 binding partner recognition.…”