Membrane lipid compositional sensing by the inducible amphipathic helix of CCT

The activation loop of PIP5K functions as a membrane sensor essential for lipid substrate processing

“…To our knowledge, this mechanism is fundamentally different from that of well-characterized membrane-associating enzymes using an amphipathic helix for membrane binding and activity regulation ( 24 – 28 ). For example, an amphipathic helix within the M domain of cytidine triphosphate:phosphocholine cytidylyltransferase plays an autoinhibitory role in the membrane-unbound state, whereas it activates the enzyme in a membrane-bound state most likely through a long-range allosteric effect ( 29 ). In addition, somehow similar to the antimicrobial peptides that fold into an amphipathic helix and disintegrate the membrane ( 30 ), the activation loop of PIP5K may also disturb the membrane integrity and facilitate binding of the head group of the lipid substrate.…”

Establishing the lipid droplet proteome: Mechanisms of lipid droplet protein targeting and degradation

“…phosphatidylserine) and a high degree of lipid packing defects, caused by the presence of unsaturated fatty acids and the general lack of cholesterol [74]. The amphipathic helix of CCT, the rate-limiting enzyme in phosphatidylcholine synthesis, and its association with membranes have been studied in detail [75]. Consistent with an important role for lipid packing in conferring binding specificity to LD proteins, CCT is activated by binding to membranes that contain high levels of lipids with smaller headgroups (e.g.…”

“…diacylglycerol and phosphatidylethanolamine), which have a conical shape that increases lipid packing defects and membrane curvature strain [65–68]. In solution, CCT’s amphipathic helix binds to its active site and inhibits its activity [75]. Insertion of the amphipathic helix into a membrane exhibiting packing defects, such as a membrane with low levels of phosphatidylcholine, anchors CCT to the membrane and relieves the helix-mediated autoinhibition of its enzymatic activity [75].…”

“…In solution, CCT’s amphipathic helix binds to its active site and inhibits its activity [75]. Insertion of the amphipathic helix into a membrane exhibiting packing defects, such as a membrane with low levels of phosphatidylcholine, anchors CCT to the membrane and relieves the helix-mediated autoinhibition of its enzymatic activity [75]. Coupling of CCT activation to membrane binding provides an elegant feedback mechanism that regulates LD size [69,70,76].…”

From yeast to humans – roles of the Kennedy pathway for phosphatidylcholine synthesis

“…The lipid bilayer is a complex assembly of over 1000 distinct molecules constantly undergoing constitutive and agonist‐stimulated synthesis and turnover, while at the same time maintaining the appropriate physical properties to act as an effective permeability barrier. Phospholipids are the main components of biological membranes while simultaneously serving as (a) second messenger molecules, (b) receptors for the recruitment of specific proteins to membranes, (c) chaperones to aid in protein folding, and (d) direct modulators of protein function . Indeed, ~ 30% of all proteins are integral membrane proteins while another ~ 30% are thought to function at a membrane surface .…”