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The University of Southampton

Research project: Attard: Physical Properties Of Biomembranes And Their Roles In Modulating The Activity Of Membrane Proteins

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Membrane phospholipid synthesis and turnover are tightly regulated and homeostatic control of membrane phospholipid content and composition are essential for cell growth and survival.

Phosphatidylcholine (PtdCho) is a major membrane phospholipid, and is a precursor to two other abundant membrane. CTP:phosphocholine cytidylyltransferase (CCT) is an extrinsic membrane protein which catalyzes a rate controlling step in PtdCho biosynthesis and the regulation of this enzyme is critical for membrane biogenesis and the production of new membrane during the S phase of the cell cycle. Binding of CCT to biomembranes induces conformational changes in the enzyme and dramatically increases the affinity of the enzyme for CTP. In contrast, CCT activation is blocked by the introduction of type I amphiphiles into the bilayer. Thus, partitioning of CCT into membranes regulates the activity of the enzyme, and hence constitutes a physical feedback signal which controls membrane phospholipid biosynthesis. Our recent work has revealed that stored curvature elasic is a novel unifying mechanism for the regulation of CCT interactions with membranes. Specifically, we have found that the activity data we obtained are consistent with the membrane/water partition coefficient for CCT being determined by both the spontaneous curvature of a monolayer and its mean curvature bending rigidity. We have shown that in the case of PC biosynthesis, a physical effect acts as the vital feedback signal which controls lipid biosynthesis. This type of feedback is quite different from those that involve specific ligand-receptor interactions. Since the activity of several other membrane-associated proteins is known to depend on the lipid composition of the host membrane, the implication of our work is that physical feedback signals that are based on the membrane elastic properties could represent a generic class of control mechanisms in metabolic and signalling pathways. Current work is aimed at exploring this exciting possibility.

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