Figure 1. Structure and regulation of SHP2.

(A) Domain architecture diagram of SHP2. Relevant mutations and the catalytic cysteine (Cys⁴⁵⁹) are indicated. (B) Auto-inhibited state of SHP2 (left, PDB: 4DGP) and representative active state of SHP2 (right, E76K mutant, PDB: 6CRF). (C) The SH2 domains of SHP2 bind to upstream phosphoproteins, inducing a conformational change that activates SHP2. (D) Rendering of auto-inhibited SHP2, highlighting several disease-associated mutation sites within (e.g. E76) and outside (e.g. T42) of the N-SH2/PTP interface (PDB: 4DGP). (E) Mutation sites in or near the N-SH2 binding pocket (PDB: 6ROY). (F) Mutation sites in or near the C-SH2 binding pocket (PDB: 6R5G). The primary specificity-determining regions of the SH2 domains, which dictate +1 to +5 residue preferences, are marked with black dashed lines.