Public Time:
2021-04-27 00:00:00
Journal:
PNAS
doi: 10.1073/pnas.2025107118
Author:
Massimiliano Anselmi,Jochen S. Hub
Summary:
SHP2 is a multidomain protein, playing an important role in upregulating cellular processes such as cell survival, proliferation, and programmed cell death. SHP2 mutations cause developmental disorders and are found in many cancer types, including neuroblastoma, breast cancer, and leukemia. In healthy cells, SHP2 mainly takes an autoinhibited, inactive form, and SHP2 is activated upon binding of phosphopeptides to the N-SH2 domain. For the past two decades, the widening of the binding cleft upon peptide binding has been considered the key event driving SHP2 activation. Here, by analyzing crystallographic data and molecular simulations, we demonstrate that the binding cleft in N-SH2 is, instead, already open and accessible in solution, and its degree of opening does not influence SHP2 activation.
All study data are included in this article and/or [ SI Appendix ][1].
[1]: https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2025107118/-/DCSupplemental