Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.18.388447v1?rss=1 Authors: Anselmi, M., Hub, J. S. 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. However, 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 {beta}-sheet of N-SH2 is the key allosteric switch triggering SHP2 activation. Copy rights belong to original authors. Visit the link for more info