Dataset Information

Insight into the PTEN - p85? interaction and lipid binding properties of the p85? BH domain.

ABSTRACT: The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in regulating cell growth and cell survival and is frequently deregulated in cancer cells. p85? regulates the p110? lipid kinase, and also stabilizes and stimulates PTEN, the lipid phosphatase that downregulates this pathway. In this report, we determined that the p85? BH domain binds several phosphorylated phosphoinositide lipids, an interaction that could help localize p85? to membranes rich in these lipids. We also identified key residues responsible for mediating PTEN - p85? complex formation. Based on these experimental results, a docking model for the PTEN - p85? BH domain complex was developed that is consistent with the known binding interactions for both PTEN and p85?. This model involves extensive side-chain and peptide backbone contacts between both the PASE and C2 domains of PTEN with the p85? BH domains. The p85? BH domain residues shown to be important for PTEN binding were p85? residues E212, Q221, K225, R228 and H234. We also verified experimentally the importance of PTEN-E91 in mediating the interaction with the p85? BH domain. These results shed new light on the mechanism of PTEN regulation by p85?.

SUBMITTER: Marshall JDS

PROVIDER: S-EPMC6319338 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Insight into the PTEN - p85α interaction and lipid binding properties of the p85α BH domain.

Marshall Jeremy D S JDS Mellor Paul P Ruan Xuan X Whitecross Dielle E DE Moore Stanley A SA Anderson Deborah H DH

Oncotarget 20181211 97

The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in regulating cell growth and cell survival and is frequently deregulated in cancer cells. p85α regulates the p110α lipid kinase, and also stabilizes and stimulates PTEN, the lipid phosphatase that downregulates this pathway. In this report, we determined that the p85α BH domain binds several phosphorylated phosphoinositide lipids, an interaction that could help localize p85α to membranes rich in these lipids. We also identified k ...[more]

PMID: 30651929

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Project description:BackgroundThe hydatid disease parasite Echinococcus granulosus has a restricted lipid metabolism, and needs to harvest essential lipids from the host. Antigen B (EgAgB), an abundant lipoprotein of the larval stage (hydatid cyst), is thought to be important in lipid storage and transport. It contains a wide variety of lipid classes, from highly hydrophobic compounds to phospholipids. Its protein component belongs to the cestode-specific Hydrophobic Ligand Binding Protein family, which includes five 8-kDa isoforms encoded by a multigene family (EgAgB1-EgAgB5). How lipid and protein components are assembled into EgAgB particles remains unknown. EgAgB apolipoproteins self-associate into large oligomers, but the functional contribution of lipids to oligomerization is uncertain. Furthermore, binding of fatty acids to some EgAgB subunits has been reported, but their ability to bind other lipids and transfer them to acceptor membranes has not been studied.Methodology/principal findingsLipid-free EgAgB subunits obtained by reverse-phase HPLC were used to analyse their oligomerization, ligand binding and membrane interaction properties. Size exclusion chromatography and cross-linking experiments showed that EgAgB8/2 and EgAgB8/3 can self-associate, suggesting that lipids are not required for oligomerization. Furthermore, using fluorescent probes, both subunits were found to bind fatty acids, but not cholesterol analogues. Analysis of fatty acid transfer to phospholipid vesicles demonstrated that EgAgB8/2 and EgAgB8/3 are potentially capable of transferring fatty acids to membranes, and that the efficiency of transfer is dependent on the surface charge of the vesicles.Conclusions/significanceWe show that EgAgB apolipoproteins can oligomerize in the absence of lipids, and can bind and transfer fatty acids to phospholipid membranes. Since imported fatty acids are essential for Echinococcus granulosus, these findings provide a mechanism whereby EgAgB could engage in lipid acquisition and/or transport between parasite tissues. These results may therefore indicate vulnerabilities open to targeting by new types of drugs for hydatidosis therapy.

Dataset Information

Insight into the PTEN - p85? interaction and lipid binding properties of the p85? BH domain.

Publications

Insight into the PTEN - p85α interaction and lipid binding properties of the p85α BH domain.

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