Membrane Hemifusion: Crossing a Chasm in Two Leaps Leonid V. Chernomordik, Michael M. Kozlov  Cell  Volume 123, Issue 3, Pages 375-382 (November 2005) DOI: 10.1016/j.cell.2005.10.015 Copyright © 2005 Elsevier Inc. Terms and Conditions

Figure 1 Fusion Pathways To illustrate the measurable hallmarks of different fusion states, the leaflets of the membrane at the top are labeled by colored probes. A blue water-soluble probe labels the aqueous volume surrounded by the membrane. (A) Direct fusion pathway. (1) The membranes are brought together by fusion proteins depicted in gray. (2) Proteins arrange into complexes and bind each other in a trans-configuration to establish a continuous connection between two protein-lined pores. This allows content mixing. (3) Expansion of the fusion pore allows lipid mixing in addition to content mixing. (B) Fusion-through-hemifusion. The proximal and distal leaflets of the membrane at the top are labeled with red and green probes, respectively. In the initial prefusion state (1), membranes are separated by an approximately 10 nm gap determined by the size of the membrane-docking proteins. (2) Proteins bring membrane bilayers into close contact. For simplicity, the proteins are not shown at the periphery of the contact zone. (3) The proximal leaflets merge into a fusion stalk (see enlargement in Figure 2A), which allows lipid mixing between these leaflets, provided that the lipid flow is not hindered by proteins surrounding the fusion site. (4) The stalk expands into a hemifusion diaphragm that either breaks to form a fusion pore allowing lipid and content mixing (5) or dissociates, yielding separated membranes and interrupting fusion at the stage detectable as complete or partial lipid mixing between the proximal membrane leaflets (6). Cell 2005 123, 375-382DOI: (10.1016/j.cell.2005.10.015) Copyright © 2005 Elsevier Inc. Terms and Conditions

Figure 2 Fusion Stalk (A) Stalk structure generated on the basis of the continuous elastic model of membrane leaflets (Kozlovsky and Kozlov, 2002). The bold solid lines indicate the membrane-water interface; the dashed lines show the bilayer midplane. A green-colored cone-shaped lipid molecule such as PE (on the left wing of the stalk) matches the stalk structure, whereas the red-colored inverted-cone-shaped lipid molecule such as LPC (on the right wing of stalk) disturbs the packing of the lipids in the stalk. (B) Stalk structure predicted by the coarse-grained molecular dynamics simulations. The magenta and red spheres represent the polar groups, whereas the green spheres correspond to the hydrophobic groups of lipid molecules; the blue spheres represent water molecules. Adapted from Marrink and Mark (2004) with permission. Cell 2005 123, 375-382DOI: (10.1016/j.cell.2005.10.015) Copyright © 2005 Elsevier Inc. Terms and Conditions