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Review
. 2016 Sep:199:136-143.
doi: 10.1016/j.chemphyslip.2016.05.003. Epub 2016 May 11.

The role of cholesterol in membrane fusion

Sung-Tae Yang  1 , Alex J B Kreutzberger  1 , Jinwoo Lee  1 , Volker Kiessling  1 , Lukas K Tamm  2
Affiliations
Review

The role of cholesterol in membrane fusion

Sung-Tae Yang et al. Chem Phys Lipids. 2016 Sep.

Abstract

Cholesterol modulates the bilayer structure of biological membranes in multiple ways. It changes the fluidity, thickness, compressibility, water penetration and intrinsic curvature of lipid bilayers. In multi-component lipid mixtures, cholesterol induces phase separations, partitions selectively between different coexisting lipid phases, and causes integral membrane proteins to respond by changing conformation or redistribution in the membrane. But, which of these often overlapping properties are important for membrane fusion?-Here we review a range of recent experiments that elucidate the multiple roles that cholesterol plays in SNARE-mediated and viral envelope glycoprotein-mediated membrane fusion.

Keywords: Cholesterol; Exocytosis; Fusion peptide; Fusion protein; Membrane fusion; SNARE; Viral envelope protein; Virus entry.

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Figures

Figure 1
Figure 1
Cholesterol has multiple effects on lipid bilayers. Cholesterol (a) changes the fluidity (b), thickness (c), compressibility (d), water penetration (e), and intrinsic curvature (f) of lipid bilayers. Cholesterol also induces phase separations in multicomponent lipid mixtures (g), partitions selectively between different coexisting lipid phases (h), and causes integral membrane proteins to respond by changing conformation (i) or redistribution (j) in the membrane.
Figure 2
Figure 2
Possible contributions of cholesterol to the regulation of membrane fusion proteins and fusion intermediates and to overcoming multiple energetic barriers of membrane fusion. The schematic diagrams illustrate a protein-assisted stalk-pore model of membrane fusion mediated by SNARE or viral envelope glycoproteins. (a) Secretory vesicles or enveloped viruses are targeted to docking and fusion sites. Cholesterol may influence lipid phase-separation, protein distribution and protein clustering, thereby affecting the docking step. (b) Interaction of at least some viral fusion peptides with the target membrane appears to be dependent on cholesterol. For example, cholesterol-mediated microdomains or clusters may facilitate the insertion of fusion peptides at domain boundaries. (c) Cholesterol can lower the energy for lipid stalk formation by providing intrinsic negative curvature. (d) The ordered structure and negative intrinsic membrane curvature of cholesterol-rich regions opposes fusion pore formation (unless cholesterol is asymmetrically distributed to the distal leaflets of the fusing membranes), but boundaries of lipid rafts and protein clusters induced by cholesterol may promote fusion pore formation in some cases. The multiple roles of cholesterol in the individual fusion steps may be oversimplified in these cartoons, but the main point is that cholesterol affects membrane fusion in multiple complex ways.
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