4DGX

LEOPARD Syndrome-Associated SHP2/Y279C mutant

4DGX の概要

• エントリーDOI: 10.2210/pdb4dgx/pdb
• 関連するPDBエントリー: 4DGP
• 分子名称: Tyrosine-protein phosphatase non-receptor type 11 (2 entities in total)
• 機能のキーワード: hydrolase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: Q06124
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 61701.61

構造登録者

Yu, Z.H.,Xu, J.,Walls, C.D.,Chen, L.,Zhang, S.,Wu, L.,Wang, L.N.,Liu, S.J.,Zhang, Z.Y. (登録日: 2012-01-27, 公開日: 2013-03-06, 最終更新日: 2024-02-28)

主引用文献

Yu, Z.H.,Xu, J.,Walls, C.D.,Chen, L.,Zhang, S.,Zhang, R.,Wu, L.,Wang, L.,Liu, S.,Zhang, Z.Y.
Structural and Mechanistic Insights into LEOPARD Syndrome-Associated SHP2 Mutations.
J.Biol.Chem., 288:10472-10482, 2013

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

PubMed: 23457302
DOI: 10.1074/jbc.M113.450023

実験手法

X-RAY DIFFRACTION (2.3 Å)