Lipids and lipid modifications in the regulation of membrane traffic

Abstract

Lipids play a multitude of roles in intracellular protein transport and membrane traffic. While a large body of data implicates phosphoinositides in these processes, much less is known about other glycerophospholipids such as phosphatidic acid, diacylglycerol, and phosphatidylserine. Growing evidence suggests that these lipids may also play an important role, either by mediating protein recruitment to membranes or by directly affecting membrane dynamics. Although membrane lipids are believed to be organized in microdomains, recent advances in cellular imaging methods paired with sophisticated reporters and proteomic analysis have led to the formulation of alternative ideas regarding the characteristics and putative functions of lipid microdomains and their associated proteins. In fact, the traditional view that membrane proteins may freely diffuse in a large 'sea of lipids' may need to be revised. Lastly, modifications of proteins by lipids or related derivatives have surprisingly complex roles on regulated intracellular transport of a wide range of molecules.

Figure 1

Pathways leading to the synthesis of the main glycerophospholipids. Kinase reactions are shown in red; phosphatase reactions are in green; phospholipases are in blue and acyl transferases are in black. Biosynthetic reactions are indicated by dotted arrows. PIK, phosphatidylinositol kinase; LPAAT, lysophosphatidic acid acyl transferase.

Figure 2. Potential forms of cholesterol-based lipid microdomains

(A) Lipid rafts represent cholesterol- and glycosphingolipid-rich membrane microdomains that have been postulated to act as sorting platforms for the concentration of signaling proteins including many lipid- or GPI-anchored proteins. In light of recent data such rafts are most likely transient, nanoscale structures. (B) Specific classes of membrane proteins depending on the chemical nature and physical properties of their transmembrane segments have been postulated to laterally organize select lipids including cholesterol (Shell protein). Coalescence of shell proteins into larger complexes could lead to the formation of nanoclusters or protein-lipid-based microdomains similar to those depicted in (A). (C) The formation of highly curved membrane microdomains might be driven by peripherally associated adaptor and scaffolding proteins, some of which are able to partition predominantly into one leaflet of the bilayer. As the surface area occupied by the cytoplasmic versus the exoplasmic leaflet differs dramatically for highly curved membrane buds and vesicles curved microdomains might require stabilization by cholesterol.