5OKM

Crystal structure of human SHIP2 Phosphatase-C2

Summary for 5OKM

• Entry DOI: 10.2210/pdb5okm/pdb
• Descriptor: 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)
• Functional Keywords: ship2, phosphatase, c2, phosphatidylinositol (3, 4, 5)-triphosphate, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytosol: O15357
• Total number of polymer chains: 8
• Total formula weight: 425407.81

Authors

Le Coq, J.,Lietha, D. (deposition date: 2017-07-25, release date: 2017-08-23, Last modification date: 2024-01-17)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.96 Å)