Untold biological processes rely on certain characteristics of cell membranes, and many diseases take advantage of specific membrane properties to distort cell walls. It has long been known that proteins regulate how lipid structures within membranes take shape, and research into managing membrane behavior, such as for anti-viral medications, assumed that as the major fact.
A team of researchers from Illinois Institute of Technology and Argonne National Lab have now discovered the opposite relationship, that lipids actually affect the shape of proteins within membranes, and so affect the shape of the membranes as well. David Gidalevitz, lead author of the study appearing in Physical Review Letters, believes that “these membrane processes are critical to many basic biological functions. Understanding them will help us to understand the biology underlying many important diseases.”
More details from Argonne:
Gp41 is responsible for binding to host membranes and creating a pore through which viral RNA is inserted into the cell to propagate the virus. At the molecular level, this means that the viral protein must insert into the membrane and induce curvature in the membrane to make the pore. Careful measurement of the way the protein inserts into the lipid monolayer allowed the team to study how lipids and proteins affect each other during the insertion process.
Surprisingly, although the researchers expected gp41 to induce curvature in the lipid monolayer to form the pore, they found that experiments in which the monolayer contained more cholesterol showed that the lipids were actually affecting the structure of the protein. That is, as cholesterol concentrations increased, the area the protein occupied diminished and the ratio of lipids to proteins increased, suggesting that the protein was compacting itself differently as it inserted into the monolayer depending on its lipid composition.
The gp41 fragment that the team used has been shown to be capable of adopting one of two different structures known as α-helix or β-sheet. Their measurements are consistent with a change from the α-helical to the β-sheet structure as the cholesterol concentration increases, as shown in the figure.
The composition of the lipid monolayer also determined how deeply the protein penetrated its surface. In monolayers that completely lacked cholesterol, the protein penetrated very shallowly, however, as cholesterol increased, the depth that the protein inserted into the monolayer increased as well.
Remarkably, the free energy required for shallow insertion into the cholesterol-free membrane was the same as that for deep insertion into the cholesterol-rich membrane suggesting the structural change in the protein helped it to overcome the greater rigidity of the cholesterol-rich membrane.
“These data suggest that the cholesterol is inducing a conformational change in the protein and we think that when cholesterol is present, the fusion protein changes to form a sort of anchor in the membrane to hold the virus in place for fusion,” said Gidalevitz, lead author of the paper published in Physical Review Letters.
Next, the group hopes to extend these findings in experiments that will adapt their technique to more complex lipid bilayers with different lipid compositions and to different proteins including the islet amyloid-forming polypeptide amylin linked to Type 2 diabetes. “These membrane processes are critical to many basic biological functions,” said Gidalevitz. “Understanding them will help us to understand the biology underlying many important diseases.”
Argonne press release: Driving Membrane Curvature
Study abstract in Physical Review Letters: Cholesterol Mediates Membrane Curvature during Fusion Events