The pathogenic E139D mutation stabilizes a non-canonical active state of the multi-domain phosphatase SHP2

Dysregulation of the phosphatase SHP2 is implicated in various diseases, including congenital disorders and cancer. SHP2 contains two phosphotyrosine-recognition domains (N-SH2 and C-SH2) and a protein tyrosine phosphatase (PTP) domain. The N-SH2 domain is critical for SHP2 regulation. In the auto-inhibited state, it binds to the PTP domain and blocks the active site, but phosphoprotein engagement destabilizes the N-SH2/PTP domain interaction, thereby exposing the active site. Many disease mutations in SHP2 are at the N-SH2/PTP interface, and they hyperactivate SHP2 by disrupting auto-inhibitory interactions. The activating E139D mutation represents an exception to this mechanism, as it resides in the C-SH2 domain and makes minimal interactions in auto-inhibited and active state crystal structures. As part of this study, we used AlphaFold2 modeling and molecular dynamics simulations to characterize an alternative active conformation of SHP2, in which Glu139 interacts with Arg4 and Arg5 on the N-SH2 domain to stabilize a novel N-SH2/C-SH2 interface. This dataset includes the molecular dynamics trajectories for the E139D mutant in this unique active conformation, as well as Python scripts used to extract select measurements from the trajectories.

Methods
The molecular dynamics data were generated using the Amber Molecular Dynamics Package. Data were processed using the CPPTRAJ program within AmberTools. Specific measurements were extracted using Python scripts using the Biopython module. These scripts and trajectory files are included in this dataset.