5OKM

Crystal structure of human SHIP2 Phosphatase-C2

5OKM の概要

• エントリーDOI: 10.2210/pdb5okm/pdb
• 分子名称: Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2, 2-[3-(2-HYDROXY-1,1-DIHYDROXYMETHYL-ETHYLAMINO)-PROPYLAMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL, NITRATE ION, ... (5 entities in total)
• 機能のキーワード: ship2, phosphatase, c2, phosphatidylinositol (3, 4, 5)-triphosphate, hydrolase
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm, cytosol: O15357
• タンパク質・核酸の鎖数: 8
• 化学式量合計: 425407.81

構造登録者

Le Coq, J.,Lietha, D. (登録日: 2017-07-25, 公開日: 2017-08-23, 最終更新日: 2024-01-17)

主引用文献

Le Coq, J.,Camacho-Artacho, M.,Velazquez, J.V.,Santiveri, C.M.,Gallego, L.H.,Campos-Olivas, R.,Dolker, N.,Lietha, D.
Structural basis for interdomain communication in SHIP2 providing high phosphatase activity.
Elife, 6:-, 2017

PubMed Abstract: SH2-containing-inositol-5-phosphatases (SHIPs) dephosphorylate the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P) and play important roles in regulating the PI3K/Akt pathway in physiology and disease. Aiming to uncover interdomain regulatory mechanisms in SHIP2, we determined crystal structures containing the 5-phosphatase and a proximal region adopting a C2 fold. This reveals an extensive interface between the two domains, which results in significant structural changes in the phosphatase domain. Both the phosphatase and C2 domains bind phosphatidylserine lipids, which likely helps to position the active site towards its substrate. Although located distant to the active site, the C2 domain greatly enhances catalytic turnover. Employing molecular dynamics, mutagenesis and cell biology, we identify two distinct allosteric signaling pathways, emanating from hydrophobic or polar interdomain interactions, differentially affecting lipid chain or headgroup moieties of PI(3,4,5)P. Together, this study reveals details of multilayered C2-mediated effects important for SHIP2 activity and points towards interesting new possibilities for therapeutic interventions.

PubMed: 28792888
DOI: 10.7554/eLife.26640

実験手法

X-RAY DIFFRACTION (1.96 Å)