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James H Hurley - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of a Phosphatidylinositol 3 phosphate specific membrane targeting motif the fyve domain of vps27p
Cell, 1999Co-Authors: Saurav Misra, James H HurleyAbstract:Abstract Phosphatidylinositol 3-phosphate regulates membrane trafficking and signaling pathways by interacting with the FYVE domains of target proteins. The 1.15 A structure of the Vps27p FYVE domain reveals two antiparallel β sheets and an α helix stabilized by two Zn 2+ -binding clusters. The core secondary structures are similar to a rabphilin-3A Zn 2+ -binding domain and to the C1 and LIM domains. Phosphatidylinositol 3-phosphate binds to a pocket formed by the (R/K)(R/K)HHCR motif. A lattice contact shows how anionic ligands can interact with the Phosphatidylinositol 3-phosphate-binding site. The tip of the FYVE domain has basic and hydrophobic surfaces positioned so that nonspecific interactions with the phospholipid bilayer can abet specific binding to Phosphatidylinositol 3-phosphate.
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Crystal structure of a Phosphatidylinositol 3-phosphate-specific membrane-targeting motif, the FYVE domain of Vps27p.
Cell, 1999Co-Authors: Saurav Misra, James H HurleyAbstract:Phosphatidylinositol 3-phosphate regulates membrane trafficking and signaling pathways by interacting with the FYVE domains of target proteins. The 1.15 A structure of the Vps27p FYVE domain reveals two antiparallel beta sheets and an alpha helix stabilized by two Zn2+-binding clusters. The core secondary structures are similar to a rabphilin-3A Zn2+-binding domain and to the C1 and LIM domains. Phosphatidylinositol 3-phosphate binds to a pocket formed by the (R/K)(R/K)HHCR motif. A lattice contact shows how anionic ligands can interact with the Phosphatidylinositol 3-phosphate-binding site. The tip of the FYVE domain has basic and hydrophobic surfaces positioned so that nonspecific interactions with the phospholipid bilayer can abet specific binding to Phosphatidylinositol 3-phosphate.
Saurav Misra - One of the best experts on this subject based on the ideXlab platform.
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crystal structure of a Phosphatidylinositol 3 phosphate specific membrane targeting motif the fyve domain of vps27p
Cell, 1999Co-Authors: Saurav Misra, James H HurleyAbstract:Abstract Phosphatidylinositol 3-phosphate regulates membrane trafficking and signaling pathways by interacting with the FYVE domains of target proteins. The 1.15 A structure of the Vps27p FYVE domain reveals two antiparallel β sheets and an α helix stabilized by two Zn 2+ -binding clusters. The core secondary structures are similar to a rabphilin-3A Zn 2+ -binding domain and to the C1 and LIM domains. Phosphatidylinositol 3-phosphate binds to a pocket formed by the (R/K)(R/K)HHCR motif. A lattice contact shows how anionic ligands can interact with the Phosphatidylinositol 3-phosphate-binding site. The tip of the FYVE domain has basic and hydrophobic surfaces positioned so that nonspecific interactions with the phospholipid bilayer can abet specific binding to Phosphatidylinositol 3-phosphate.
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Crystal structure of a Phosphatidylinositol 3-phosphate-specific membrane-targeting motif, the FYVE domain of Vps27p.
Cell, 1999Co-Authors: Saurav Misra, James H HurleyAbstract:Phosphatidylinositol 3-phosphate regulates membrane trafficking and signaling pathways by interacting with the FYVE domains of target proteins. The 1.15 A structure of the Vps27p FYVE domain reveals two antiparallel beta sheets and an alpha helix stabilized by two Zn2+-binding clusters. The core secondary structures are similar to a rabphilin-3A Zn2+-binding domain and to the C1 and LIM domains. Phosphatidylinositol 3-phosphate binds to a pocket formed by the (R/K)(R/K)HHCR motif. A lattice contact shows how anionic ligands can interact with the Phosphatidylinositol 3-phosphate-binding site. The tip of the FYVE domain has basic and hydrophobic surfaces positioned so that nonspecific interactions with the phospholipid bilayer can abet specific binding to Phosphatidylinositol 3-phosphate.
Philip W. Majerus - One of the best experts on this subject based on the ideXlab platform.
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Cell lines from kidney proximal tubules of a patient with Lowe syndrome lack OCRL inositol polyphosphate 5-phosphatase and accumulate Phosphatidylinositol 4,5-bisphosphate.
Journal of Biological Chemistry, 1998Co-Authors: Xiaoling Zhang, Patricia A. Hartz, Elizabeth T. Philip, Lorraine C. Racusen, Philip W. MajerusAbstract:The protein product of the gene that when mutated is responsible for Lowe syndrome, or oculocerebrorenal syndrome (OCRL), is an inositol polyphosphate 5-phosphatase. It has a marked preference for Phosphatidylinositol 4,5-bisphosphate although it hydrolyzes all four of the known inositol polyphosphate 5-phosphatase substrates: inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate, Phosphatidylinositol 4,5-bisphosphate, and Phosphatidylinositol 3,4,5-trisphosphate. The enzyme activity of this protein is determined by a region of 672 out of a total of 970 amino acids that is homologous to inositol polyphosphate 5-phosphatase II. Cell lines from kidney proximal tubules of a patient with Lowe syndrome and a normal individual were used to study the function of OCRL. The cells from the Lowe syndrome patient lack OCRL protein. OCRL is the major Phosphatidylinositol 4,5-bisphosphate 5-phosphatase in these cells. As a result, these cells accumulate Phosphatidylinositol 4,5-bisphosphate even though at least four other inositol polyphosphate 5-phosphatase isozymes are present in these cells. OCRL is associated with lysosomal membranes in control proximal tubule cell lines suggesting that OCRL may function in lysosomal membrane trafficking by regulating the specific pool of Phosphatidylinositol 4,5-bisphosphate that is associated with lysosomes.
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Phosphatidylinositol-4-phosphate 5-kinase isozymes catalyze the synthesis of 3-phosphate-containing Phosphatidylinositol signaling molecules.
Journal of Biological Chemistry, 1997Co-Authors: Xiaoling Zhang, Philip W. Majerus, Joost C. Loijens, Igor V. Boronenkov, F. Anderson Norris, Oliver Thum, Gregory J Parker, Glenn D Prestwich, Jian Chen, Richard A AndersonAbstract:Abstract Phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks) utilize Phosphatidylinositols containing D-3-position phosphates as substrates to form Phosphatidylinositol 3,4-bisphosphate. In addition, type I PIP5Ks phosphorylate Phosphatidylinositol 3,4-bisphosphate to Phosphatidylinositol 3,4,5-trisphosphate, while type II kinases have less activity toward this substrate. Remarkably, these kinases can convert Phosphatidylinositol 3-phosphate to Phosphatidylinositol 3,4,5-trisphosphate in a concerted reaction. Kinase activities toward the 3-position phosphoinositides are comparable with those seen with Phosphatidylinositol 4-phosphate as the substrate. Therefore, the PIP5Ks can synthesize Phosphatidylinositol 4,5-bisphosphate and two 3-phosphate-containing polyphosphoinositides. These unexpected activities position the PIP5Ks as potential participants in the generation of all polyphosphoinositide signaling molecules.
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nuclear Phosphatidylinositols decrease during s phase of the cell cycle in hela cells
Journal of Biological Chemistry, 1994Co-Authors: John D York, Philip W. MajerusAbstract:In the current study we have measured Phosphatidylinositols during the cell cycle. HeLa cells were labeled with [3H]myoinositol to a steady state, synchronized to the G1/S boundary, and the levels of Phosphatidylinositol (PtdIns) lipids were measured at various times after release from the block. The levels of total cellular PtdIns, PtdIns(4)P, and PtdIns(4,5)P2 relative to total cellular phospholipid did not vary throughout the cell cycle. We then isolated nuclei from synchronized cells using a non-detergent method and found that the levels of nuclear PtdIns lipids decreased by over 50% at 2 and 4 h after release from the G1/S boundary (S-phase of the cell cycle) and returned to the original levels by 9 h. Separation of individual inositol-containing nuclear lipids showed that PtdIns decreased by 50% while levels of PtdIns(4)P and PtdIns(4,5)P2 decreased by 66%. Levels of the cytoplasmic PtdIns lipids remained constant throughout this period. This experiment indicates that there is specific nuclear. PtdIns turnover that is activated during DNA synthesis.
Emilio Hirsch - One of the best experts on this subject based on the ideXlab platform.
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spatiotemporal control of endocytosis by Phosphatidylinositol 3 4 bisphosphate
Nature, 2013Co-Authors: York Posor, Marielle Eichhorngruenig, Dmytro Puchkov, Johannes Schoneberg, Alexander Ullrich, Andre Lampe, Rainer Muller, Sirus Zarbakhsh, Federico Gulluni, Emilio HirschAbstract:Phosphoinositides are important regulators of intracellular membrane traffic, and although the role of PI(4,5)P2 has been well characterised, the function of PI(3,4)P2 remains unclear; here the formation of PI(3,4)P2 by the class II Phosphatidylinositol-3-kinase C2α enzyme is shown to control clathrin-mediated endocytosis. Phosphoinositides are important regulators of intracellular membrane traffic. Although the role of Phosphatidylinositol-4,5-bisphosphate has been well characterized, that of Phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) remains unclear. In this study, Volker Haucke and colleagues show that formation of PI(3,4)P2 by the class II Phosphatidylinositol-3-kinase C2α (PI(3)K C2α) enzyme spatiotemporally controls clathrin-mediated endocytosis. These findings present a novel function of PI(3,4)P2 in membrane traffic. Phosphoinositides serve crucial roles in cell physiology, ranging from cell signalling to membrane traffic1,2. Among the seven eukaryotic phosphoinositides the best studied species is Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), which is concentrated at the plasma membrane where, among other functions, it is required for the nucleation of endocytic clathrin-coated pits3,4,5,6. No Phosphatidylinositol other than PI(4,5)P2 has been implicated in clathrin-mediated endocytosis, whereas the subsequent endosomal stages of the endocytic pathway are dominated by Phosphatidylinositol-3-phosphates(PI(3)P)7. How Phosphatidylinositol conversion from PI(4,5)P2-positive endocytic intermediates to PI(3)P-containing endosomes is achieved is unclear. Here we show that formation of Phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) by class II Phosphatidylinositol-3-kinase C2α (PI(3)K C2α) spatiotemporally controls clathrin-mediated endocytosis. Depletion of PI(3,4)P2 or PI(3)K C2α impairs the maturation of late-stage clathrin-coated pits before fission. Timed formation of PI(3,4)P2 by PI(3)K C2α is required for selective enrichment of the BAR domain protein SNX9 at late-stage endocytic intermediates. These findings provide a mechanistic framework for the role of PI(3,4)P2 in endocytosis and unravel a novel discrete function of PI(3,4)P2 in a central cell physiological process.
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spatiotemporal control of endocytosis by Phosphatidylinositol 3 4 bisphosphate
Nature, 2013Co-Authors: York Posor, Marielle Eichhorngruenig, Dmytro Puchkov, Johannes Schoneberg, Alexander Ullrich, Andre Lampe, Rainer Muller, Sirus Zarbakhsh, Federico Gulluni, Emilio HirschAbstract:Phosphoinositides serve crucial roles in cell physiology, ranging from cell signalling to membrane traffic. Among the seven eukaryotic phosphoinositides the best studied species is Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2), which is concentrated at the plasma membrane where, among other functions, it is required for the nucleation of endocytic clathrin-coated pits. No Phosphatidylinositol other than PI(4,5)P2 has been implicated in clathrin-mediated endocytosis, whereas the subsequent endosomal stages of the endocytic pathway are dominated by Phosphatidylinositol-3-phosphates(PI(3)P). How Phosphatidylinositol conversion from PI(4,5)P2-positive endocytic intermediates to PI(3)P-containing endosomes is achieved is unclear. Here we show that formation of Phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2) by class II Phosphatidylinositol-3-kinase C2α (PI(3)K C2α) spatiotemporally controls clathrin-mediated endocytosis. Depletion of PI(3,4)P2 or PI(3)K C2α impairs the maturation of late-stage clathrin-coated pits before fission. Timed formation of PI(3,4)P2 by PI(3)K C2α is required for selective enrichment of the BAR domain protein SNX9 at late-stage endocytic intermediates. These findings provide a mechanistic framework for the role of PI(3,4)P2 in endocytosis and unravel a novel discrete function of PI(3,4)P2 in a central cell physiological process.
Daniel Broek - One of the best experts on this subject based on the ideXlab platform.
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control of intramolecular interactions between the pleckstrin homology and dbl homology domains of vav and sos1 regulates rac binding
Journal of Biological Chemistry, 2000Co-Authors: Balaka Das, Xiaodong Shu, Gwojen Day, Jaewon Han, Murali U Krishna, John R Falck, Daniel BroekAbstract:Vav and Sos1 are Dbl family guanine nucleotide exchange factors, which activate Rho family GTPases in response to Phosphatidylinositol 3-kinase products. A pleckstrin homology domain adjacent to the catalytic Dbl homology domain via an unknown mechanism mediates the effects of phosphoinositides on guanine nucleotide exchange activity. Here we tested the possibility that Phosphatidylinositol 3-kinase substrates and products control an interaction between the pleckstrin homology domain and the Dbl homology domain, thereby explaining the inhibitory effects of Phosphatidylinositol 3-kinase substrates and stimulatory effects of the products. Binding studies using isolated fragments of Vav and Sos indicate Phosphatidylinositol 3-kinase substrate promotes the binding of the pleckstrin homology domain to the Dbl homology domain and blocks Rac binding to the DH domain, whereas Phosphatidylinositol 3-kinase products disrupt the Dbl homology/pleckstrin homology interactions and permit Rac binding. Additionally, Lck phosphorylation of Vav, a known activating event, reduces the affinities between the Vav Dbl homology and pleckstrin homology domains and permits Rac binding. We also show Vav activation in cells, as monitored by phosphorylation of Vav, Vav association with Phosphatidylinositol 3,4,5-trisphosphate, and Vav guanine nucleotide exchange activity, is blocked by the Phosphatidylinositol 3-kinase inhibitor wortmannin. These results suggest the molecular mechanisms for activation of Vav and Sos1 require disruption of inhibitory intramolecular interactions involving the pleckstrin homology and Dbl homology domains.
