Structural and Mechanistic Insights into LEOPARD Syndrome-Associated SHP2 Mutations

• DOI: 10.1074/jbc.m113.450023
• Publication Date: 2013-03-02T12:16:23Z
• Authors: Zhi-Hong Yu; Jie Xu; Chad D. Walls; Lan Chen; Sheng Zhang; Ruoyu Zhang; Li Wu; Lina Wang; Sijiu Liu; Zhong-Yin Zhang
• Keywords: PTPN11; Noonan Syndrome; Leopard; Loss function

SHP2 is an allosteric phosphatase essential for growth factor-mediated Ras activation. Germ-line mutations in cause clinically similar LEOPARD and Noonan syndromes, two of several autosomal-dominant conditions characterized by gain-of-function the pathway. Interestingly, syndrome mutants are constitutively active, whereas exhibit reduced activity. How do catalytically impaired engender phenotypes? Our study reveals that weaken intramolecular interaction between N-SH2 domains, leading to a change molecular switching mechanism. Consequently, bind upstream activators preferentially hypersensitive factor stimulation. They also stay longer with scaffolding adapters, thus prolonging substrate turnover, which compensates The provides solid framework understanding how individual diseases.