(a) Because new lipid molecules are added only to the cytosolic half of the er membrane bilayer and lipid molecules do not flip spontaneously from one monolayer to the other, a transmembrane phospholipid translocator (called a scramblase) is required to transfer lipid molecules from the cytosolic half to the lumenal half so that the membrane grows as a bilayer. The scramblase is not specific for particular phospholipid head groups and therefore equilibrates the different phospholipids between the two monolayers. (B) fueled by aTp hydrolysis, a head-group-specific flippase in the plasma membrane actively flips phosphatidylserine and phosphatidylethanolamine directionally from the extracellular to the cytosolic leaflet, creating the characteristically asymmetric lipid bilayer of the plasma membrane of animal cells (see figure 10–15).
Figure 12–55 The structure of ceramide.
As discussed in Chapter 13, the plasma membrane and the membranes of the Golgi apparatus, lysosomes, and endosomes all form part of a membrane system that communicates with the ER by means of transport vesicles, which transfer both proteins and lipids. Mitochondria and plastids, however, do not belong to this system, and they therefore require different mechanisms to import proteins and lipids for growth. We have already seen that they import most of their proteins from the cytosol. Although mitochondria modify some of the lipids they import, they do not synthesize lipids de novo; instead, their lipids have to be imported from the ER, either directly or indirectly by way of other cell membranes. In either case, special mechanisms are required for the transfer.
The details of how lipid distribution between different membranes is catalyzed and regulated are not known. Water-soluble carrier proteins called phospholipid exchange proteins (or phospholipid transfer proteins) are thought to transfer individual phospholipid molecules between membranes, functioning much like fatty acid binding proteins that shepherd fatty acids through the cytosol (see Figure 12–54). In addition, mitochondria are often seen in close juxtaposition to ER membranes in electron micrographs, and specific junction complexes have been identified that hold the ER and outer mitochondrial membrane in close proximity. It is thought that these junction complexes provide specific contact-dependent lipid transfer mechanisms that operate between these adjacent membranes.
The extensive ER network serves as a factory for the production of almost all of the cell’s lipids. In addition, a major portion of the cell’s protein synthesis occurs on the cytosolic surface of the rough ER: virtually all proteins destined for secretion or for the ER itself, the Golgi apparatus, the lysosomes, the endosomes, and the plasma membrane are first imported into the ER from the cytosol. In the ER lumen, the proteins fold and oligomerize, disulfide bonds are formed, and N-linked oligosaccharides are added. The pattern of N-linked glycosylation is used to indicate the extent of protein folding, so that proteins leave the ER only when they are properly folded. Proteins that do not fold or oligomerize correctly are translocated back into the cytosol, where they are deglycosylated, polyubiquitylated, and degraded in proteasomes. If misfolded proteins accumulate in excess in the ER, they trigger an unfolded protein response, which activates appropriate genes in the nucleus to help the ER cope.
Only proteins that carry a special ER signal sequence are imported into the ER. The signal sequence is recognized by a signal-recognition particle (SRP), which binds both the growing polypeptide chain and the ribosome and directs them to a receptor protein on the cytosolic surface of the rough ER membrane. This binding to the ER membrane initiates the translocation process that threads a loop of polypeptide chain across the ER membrane through the hydrophilic pore of a protein translocator.