Structural Biochemistry/Lipid-Dependent Membrane Protein Topogenesis

Role of Phospholipids
The main role of phospholipids in cells and organelles is to help create the permeable bilayer that separates everything inside the cell and organelles with things outside. The lipid bilayer is a support structure that is crucial for proteins involved in many diverse and important cellular processes. The diverse nature of lipid structures allows for a diverse set of chemical and physical properties within the membrane bilayer. These properties include, but are not limited to, hydrophilic and hydrophobic surfaces and electric potential that affects the folding and orientation of membrane proteins. All of these properties make it difficult to define the function of lipids in cellular processes because altering the membrane lipid composition could result in negative consequences. These difficulties have forced most studies of membrane protein topogenesis to treat the lipid bilayer as a passive amphipathic structure rather than to consider what its role is in protein organization.

The majority of important membrane proteins are composed of α-helical transmembrane domains. These transmembrane domains are located all over the membrane and are connected by hydrophilic loops. Transmembrane domains are usually allowed to take several conformations before settling on an intermediate or final transmembrane orientation, but the folding pathways must follow a very particular route after the clearance of a translocon. Depending on their affinity for the hydrophobic core of the membrane, transmembrane domains will partially pass through the bilayer. What this shows is that early transmembrane domain events are all subject to influence by the physical properties of any surrounding lipids.

Properties of Lipids that Affect Topology and Function
There any many structural, chemical, and phase-forming features of lipid molecules that are important during topogenesis. In the case of E. coli, large-scale changes to its original lipid composition has no affects on viability. The introduction of foreign lipids into the membrane of E. coli is also not only tolerated but actually improves the growth and functional properties of strains that do not have native lipids. These studies give light to the possibility of studying the properties of lipids that support native topology of other domains that are lipid sensitive. Through studies of charge retention, it is shown that the property most important to the governing of topology is the membrane bilayer's ability to balance anionic and neutrally charged lipids.

Specific Role of Membrane Lipids in Topogenesis
The discovery of a specific role for membrane lipids during topogenesis is mostly due to experiments with strains of E. coli. Certain strains of E. coli were developed with the intention of controlling the membrane phospholipid composition of the strain while maintaining the viability of the cell. The first indication that lipid-protein interactions affect topogenesis was made apparent when studies showed that the net charge of the E. coli phospholipid bilayer could be changed in a mutant. This gene was controlled and further studied to suggest that charge interactions between lipids and proteins help decide protein topology. In this way, it is shown that lipids appear to help membrane protein refolding in vitro and folding in vivo into a native conformation. This is achieved through interactions that are close to those of other protein chaperones.