In:
eLife, eLife Sciences Publications, Ltd, Vol. 6 ( 2017-08-09)
Abstract:
SH2-containing-inositol-5-phosphatases (SHIPs) dephosphorylate the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) 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)P3. Together, this study reveals details of multilayered C2-mediated effects important for SHIP2 activity and points towards interesting new possibilities for therapeutic interventions.
Type of Medium:
Online Resource
ISSN:
2050-084X
DOI:
10.7554/eLife.26640.001
DOI:
10.7554/eLife.26640.002
DOI:
10.7554/eLife.26640.003
DOI:
10.7554/eLife.26640.004
DOI:
10.7554/eLife.26640.005
DOI:
10.7554/eLife.26640.006
DOI:
10.7554/eLife.26640.007
DOI:
10.7554/eLife.26640.008
DOI:
10.7554/eLife.26640.009
DOI:
10.7554/eLife.26640.010
DOI:
10.7554/eLife.26640.011
DOI:
10.7554/eLife.26640.012
DOI:
10.7554/eLife.26640.013
DOI:
10.7554/eLife.26640.014
DOI:
10.7554/eLife.26640.015
DOI:
10.7554/eLife.26640.016
DOI:
10.7554/eLife.26640.017
DOI:
10.7554/eLife.26640.018
DOI:
10.7554/eLife.26640.019
DOI:
10.7554/eLife.26640.020
DOI:
10.7554/eLife.26640.021
DOI:
10.7554/eLife.26640.022
DOI:
10.7554/eLife.26640.023
DOI:
10.7554/eLife.26640.024
DOI:
10.7554/eLife.26640.025
DOI:
10.7554/eLife.26640.026
DOI:
10.7554/eLife.26640.027
DOI:
10.7554/eLife.26640.028
DOI:
10.7554/eLife.26640.029
DOI:
10.7554/eLife.26640.030
DOI:
10.7554/eLife.26640.031
DOI:
10.7554/eLife.26640.032
DOI:
10.7554/eLife.26640.033
DOI:
10.7554/eLife.26640.034
DOI:
10.7554/eLife.26640.035
DOI:
10.7554/eLife.26640.037
DOI:
10.7554/eLife.26640.038
DOI:
10.7554/eLife.26640.036
Language:
English
Publisher:
eLife Sciences Publications, Ltd
Publication Date:
2017
detail.hit.zdb_id:
2687154-3
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