The loops of the N-SH2 binding cleft do not serve as allosteric switch in SHP2 activation

Abstract

SHP2 is a critical regulator of signal transduction implicated in developmental disorders and cancer. SHP2 is activated by phosphopeptide binding to the N-SH2 domain, triggering the release of N-SH2 from the catalytic PTP domain. Based on early crystallographic data, it has been widely accepted that opening of the binding cleft of N-SH2 serves as a key "allosteric switch" for SHP2 activation. We critically review structural data and use extensive molecular simulations to test the "allosteric switch" model of activation. We find that the binding cleft in N-SH2 is constitutively flexible and open in solution, and that a closed cleft found in certain structures has been imposed by crystal contacts. The free energy cost for N-SH2 release is only marginally influenced by the binding cleft. We conclude that not the N-SH2 binding cleft but instead the opening of a central β-sheet of N-SH2 is the key allosteric switch triggering SHP2 activation.

How a single mutation alters the protein structure: a simulation investigation on protein tyrosine phosphatase SHP2

“…14 Recent investigations on the activation mechanism of SHP2 proposed that the key allosteric switch triggering SHP2 activation might not be the widely-accepted opening of the N-SH2 binding cleft but the opening of the central beta-sheet of N-SH2 based on extensive molecule dynamics (MD) simulations and free energy calculations. 15,16…”

“…14 Recent investigations on the activation mechanism of SHP2 proposed that the key allosteric switch triggering SHP2 activation might not be the widely-accepted opening of the N-SH2 binding cle but the opening of the central beta-sheet of N-SH2 based on extensive molecule dynamics (MD) simulations and free energy calculations. 15,16 Distinct from the SHP2-WT in the autoinhibited inactivate state, SHP2 with oncogenic mutations shows enhanced basal activity without the stimulation of tyrosine-phosphorylated peptides. 17 The X-ray structure of SHP2 with the E76K mutation (SHP2-E76K), one of the most frequently observed oncogenic mutations, reveals that the N-SH2 domain locates far away from the catalytic pocket of the PTP domain hence the catalytic site is fully exposed to the solvent (PDB id: 6CRF).…”