Data from: Revealing the principles of inter- and intra-domain regulation in a signaling enzyme via scanning mutagenesis

Multi-domain enzymes can be regulated both by inter-domain interactions
and structural features intrinsic to the catalytic domain. The tyrosine
phosphatase SHP2 is a quintessential example of a multi-domain protein
that is regulated by inter-domain interactions. This enzyme has a protein
tyrosine phosphatase (PTP) domain and two phosphotyrosine-recognition
domains (N-SH2 and C-SH2) that regulate phosphatase activity through
autoinhibitory interactions. SHP2 is canonically activated by
phosphoprotein binding to the SH2 domains, which causes large interdomain
rearrangements, but autoinhibition is also disrupted by disease-associated
mutations. Many details of the SHP2 activation are still unclear, the
structure of the active state remains elusive, and hundreds of human
variants of SHP2 have not been functionally characterized. Here, we
perform scanning mutagenesis on both full-length SHP2 and its isolated PTP
domain to examine mutational effects on inter-domain regulation and
catalytic activity. Our experiments provide a comprehensive map of SHP2
mutational sensitivity, both in the presence and absence of interdomain
regulation. Coupled with molecular dynamics simulations, our investigation
reveals novel structural features that govern the stability of the
autoinhibited and active states of SHP2. Our analysis also identifies key
residues beyond the SHP2 active site that control PTP domain dynamics and
intrinsic catalytic activity. This work expands our understanding of SHP2
regulation and provides new insights into SHP2 pathogenicity.