6ATD

Oxidized SHP2 forms a disulfide bond between Cys367 and Cys459

6ATD の概要

• エントリーDOI: 10.2210/pdb6atd/pdb
• 分子名称: Tyrosine-protein phosphatase non-receptor type 11, PHOSPHATE ION (3 entities in total)
• 機能のキーワード: hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 121524.41

構造登録者

Page, R.,Peti, W.,Critton, D.A. (登録日: 2017-08-28, 公開日: 2018-07-11, 最終更新日: 2024-11-13)

主引用文献

Machado, L.E.S.F.,Critton, D.A.,Page, R.,Peti, W.
Redox Regulation of a Gain-of-Function Mutation (N308D) in SHP2 Noonan Syndrome.
ACS Omega, 2:8313-8318, 2017

PubMed Abstract: SHP2 (Src homology 2 domain-containing protein tyrosine phosphatase 2; PTPN11) is a ubiquitous multidomain, nonreceptor protein tyrosine phosphatase (PTP) that plays an important role in diseases such as cancer, diabetes, and Noonan syndrome (NS). NS is one of the most common genetic disorders associated with congenital heart disease, and approximately half of the patients with Noonan syndrome have gain-of-function mutations in SHP2. One of the most common NS mutations is N308D. The activity of SHP2, like that of most PTPs, is reversibly inactivated by reactive oxygen species (ROS). However, the molecular basis of this inactivation and the consequences of NS-related mutations in PTPN11 on ROS-mediated inhibition are poorly understood. Here, we investigated the mechanistic and structural details of the reversible oxidation of the NS variant SHP2. We show that SHP2 is more sensitive to oxidation when compared with wild-type SHP2. We also show that although the SHP2 catalytic domain can be reactivated by dithiothreitol as effectively as the wild-type, full-length SHP2 is only poorly reactivated by comparison. To understand the mechanism of oxidation at a molecular level, we determined the crystal structure of oxidized SHP2. The structure shows that the catalytic Cys459 residue forms a disulfide bond with Cys367, which confirms that Cys367 functions as the "backdoor" cysteine in SHP2. Together, our data suggest that the reversible oxidation of SHP2 contributes negligibly, if at all, to the symptoms associated with NS.

PubMed: 29214238
DOI: 10.1021/acsomega.7b01318

実験手法

X-RAY DIFFRACTION (2.5 Å)