2026-08-05T09:54:15Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/71322024-11-29T14:35:44Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Le Coq, Johanne
author
Camacho-Artacho, Marta
author
Velázquez, José Vicente
author
Santiveri, Clara M
author
Gallego, Luis Heredia
author
Campos Olivas, Ramon
author
Dölker, Nicole
author
Lietha, Daniel
funder
Ministerio de Economía y Competitividad (España)
funder
Comunidad de Madrid (España)
2019-02-06T10:51:55Z
2019-02-06T10:51:55Z
2017
Elife. 2017;6; pii: e26640.
10.7554/eLife.26640
2050-084X
2050-084X
eLife
28792888
http://hdl.handle.net/20.500.12105/7132
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.
eng
C2 domain
E. coli
Inositol phosphatase
allosteric regulation
biochemistry
biophysics
enzyme kinetics
human
phosphatidylinositol-3,4,5-trisphosphate
structural biology
Structural basis for interdomain communication in SHIP2 providing high phosphatase activity
journal article
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https://repisalud.isciii.es/bitstreams/5da9714f-e25a-41c1-9dec-4780d1e3c2f8/download
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001a40d21db4679681785a9400d141ea
5576427
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Structuralbasisforinterdomain_2017.pdf
URL
https://repisalud.isciii.es/bitstreams/ba31fe36-77d0-481c-8765-7b351c645783/download
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6b6d6c51dc91a456a7fd64493566029e
96198
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Structuralbasisforinterdomain_2017.pdf.txt