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Regulation of PLCβ2 by the electrostatic and mechanical properties of lipid bilayers.

Arduin A, Gaffney PR, Ces O - Sci Rep (2015)

Bottom Line: However, the regulatory mechanism of PLC is not yet understood in detail.Evidence was found for a direct interaction between PLC and the GTPases that mediate phospholipase activation.PLC activity was found to depend upon the electrostatic potential and the stored curvature elastic stress of the lipid membranes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Chemical Biology, Department of Chemical Biology, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom.

ABSTRACT
Phosphoinositide-specific phospholipase C (PLC) is an important family of enzymes constituting a junction between phosphoinositide lipid signaling and the trans-membrane signal transduction processes that are crucial to many living cells. However, the regulatory mechanism of PLC is not yet understood in detail. To address this issue, activity studies were carried out using lipid vesicles in a model system that was specifically designed to study protein-protein and lipid-protein interactions in concert. Evidence was found for a direct interaction between PLC and the GTPases that mediate phospholipase activation. Furthermore, for the first time, the relationships between PLC activity and substrate presentation in lipid vesicles of various sizes, as well as lipid composition and membrane mechanical properties, were analyzed. PLC activity was found to depend upon the electrostatic potential and the stored curvature elastic stress of the lipid membranes.

No MeSH data available.


Related in: MedlinePlus

Structures of PLCβ2 obtained in isolation (lower; PDB ID = 2ZKM)4 and GTP-bound Rac1 (upper; PDB ID = 2FJU)5 illustrating the auto-inhibitory model.Rac1 switch1 is in green, switch 2 is in pink, and the X-Y linker is in red.
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f1: Structures of PLCβ2 obtained in isolation (lower; PDB ID = 2ZKM)4 and GTP-bound Rac1 (upper; PDB ID = 2FJU)5 illustrating the auto-inhibitory model.Rac1 switch1 is in green, switch 2 is in pink, and the X-Y linker is in red.

Mentions: Phosphoinositide-specific phospholipase C (PLC) is an intensively studied family of enzymes that regulates important cellular processes through their pivotal roles in trans-membrane signal transduction and phosphoinositide lipid signaling123. PLCs catalyze the hydrolysis of phosphatidylinositol 4,5-diphosphate [PtdIns(4,5)P2] to diacylglycerol and myo-inositol 1,4,5-triphosphate (IP3), which are both well known intracellular second messengers. PLCs are activated in response to the stimulation of cell surface receptors at the plasma membrane, after which the signals are carried downstream by other transducers, such as small GTPases. GTPases bound to guanosine triphosphate (GTP) induce translocation of PLC from the cytosol to the plasma membrane where the substrate of PLC is localized. However, this PLC-GTPase interaction is thought to be insufficient to cause full PLC activation. Instead, it has been proposed that a concomitant PLC-GTPase and PLC-lipid interaction is necessary to fully activate PLC, as described by the auto-inhibitory model (Fig. 1)4. According to this model, the linker between the X and Y halves of the PLC catalytic domain occludes the catalytic site. Upon binding to the GTPase, PLC translocates to the plasma membrane. It also changes conformation due to charge repulsion between the negatively charged X-Y linker and the negatively charged plasma membrane, augmented by steric compression between the X-Y linker and the membrane interface. As a result of this conformational rearrangement, the catalytic pocket of PLC finally becomes accessible to its PtdIns(4,5)P2 substrate4.


Regulation of PLCβ2 by the electrostatic and mechanical properties of lipid bilayers.

Arduin A, Gaffney PR, Ces O - Sci Rep (2015)

Structures of PLCβ2 obtained in isolation (lower; PDB ID = 2ZKM)4 and GTP-bound Rac1 (upper; PDB ID = 2FJU)5 illustrating the auto-inhibitory model.Rac1 switch1 is in green, switch 2 is in pink, and the X-Y linker is in red.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525138&req=5

f1: Structures of PLCβ2 obtained in isolation (lower; PDB ID = 2ZKM)4 and GTP-bound Rac1 (upper; PDB ID = 2FJU)5 illustrating the auto-inhibitory model.Rac1 switch1 is in green, switch 2 is in pink, and the X-Y linker is in red.
Mentions: Phosphoinositide-specific phospholipase C (PLC) is an intensively studied family of enzymes that regulates important cellular processes through their pivotal roles in trans-membrane signal transduction and phosphoinositide lipid signaling123. PLCs catalyze the hydrolysis of phosphatidylinositol 4,5-diphosphate [PtdIns(4,5)P2] to diacylglycerol and myo-inositol 1,4,5-triphosphate (IP3), which are both well known intracellular second messengers. PLCs are activated in response to the stimulation of cell surface receptors at the plasma membrane, after which the signals are carried downstream by other transducers, such as small GTPases. GTPases bound to guanosine triphosphate (GTP) induce translocation of PLC from the cytosol to the plasma membrane where the substrate of PLC is localized. However, this PLC-GTPase interaction is thought to be insufficient to cause full PLC activation. Instead, it has been proposed that a concomitant PLC-GTPase and PLC-lipid interaction is necessary to fully activate PLC, as described by the auto-inhibitory model (Fig. 1)4. According to this model, the linker between the X and Y halves of the PLC catalytic domain occludes the catalytic site. Upon binding to the GTPase, PLC translocates to the plasma membrane. It also changes conformation due to charge repulsion between the negatively charged X-Y linker and the negatively charged plasma membrane, augmented by steric compression between the X-Y linker and the membrane interface. As a result of this conformational rearrangement, the catalytic pocket of PLC finally becomes accessible to its PtdIns(4,5)P2 substrate4.

Bottom Line: However, the regulatory mechanism of PLC is not yet understood in detail.Evidence was found for a direct interaction between PLC and the GTPases that mediate phospholipase activation.PLC activity was found to depend upon the electrostatic potential and the stored curvature elastic stress of the lipid membranes.

View Article: PubMed Central - PubMed

Affiliation: Institute of Chemical Biology, Department of Chemical Biology, Imperial College London, Exhibition Road, London SW7 2AZ, United Kingdom.

ABSTRACT
Phosphoinositide-specific phospholipase C (PLC) is an important family of enzymes constituting a junction between phosphoinositide lipid signaling and the trans-membrane signal transduction processes that are crucial to many living cells. However, the regulatory mechanism of PLC is not yet understood in detail. To address this issue, activity studies were carried out using lipid vesicles in a model system that was specifically designed to study protein-protein and lipid-protein interactions in concert. Evidence was found for a direct interaction between PLC and the GTPases that mediate phospholipase activation. Furthermore, for the first time, the relationships between PLC activity and substrate presentation in lipid vesicles of various sizes, as well as lipid composition and membrane mechanical properties, were analyzed. PLC activity was found to depend upon the electrostatic potential and the stored curvature elastic stress of the lipid membranes.

No MeSH data available.


Related in: MedlinePlus