|Membrane merging intermediates of extracellular vesicles (Nat Comm 5:3912)
Dr, Wellcome Trust and The Royal Society Sir Henry Dale Fellow
Membrane fusion is a central process for all eukaryotic cells that are not only surrounded by membrane but also using membranes to form cellular compartments. Membrane merging or fusion is important for organelle formation and trafficking within the cell but also some important cells fuse as part of their function.
Biological membrane fusion is widely assumed to follow a pathway that is controlled by the action of specialised proteins called fusogens that lower the energy barrier of the process, and drive membrane bilayer rearrangements that result in merging of the membranes. The 3D structures of a substantial number of viral fusogens have been determined by X-ray crystallography, and several different basic architectures of fusogens have been described. These structures have contributed valuable insights into the mechanism of protein-mediated fusion. In particular, the different conformational states described, namely pre-fusion and post-fusion conformations, have provided an insight into the refolding of the fusogen that provides the energy for membrane fusion. However, all the published X-ray structures are of truncated fusogens devoid of the membrane bilayers whose fusion they promotes. This constitutes a fundamental shortcoming in interpreting how the fusogens mediate the bilayer rearrangement that results in fusion.
The principal thrust of the research group is studying fusion machineries in the context of the membranes. A hybrid structural approach is applied using electron cryo microscopy (CryoEM) and electron cryo tomography (cryoET) as core techniques. CryoEM and cryoET are ideally suited techniques for studying macromolecules, and the processes in which they are involved, in their native cellular and sub-cellular contexts. Super-resolution fluorescence microscopy, crystallography and biophysics are complementing techniques applied.
The study aims to pave the way for molecular intervention in membrane fusion, e.g drug delivery and anti-viral agents.
Two distinct trimeric conformations of natively membrane-anchored full-length herpes simplex virus 1 glycoprotein B.
Zeev-Ben-Mordehai T. et al, (2016), Proc Natl Acad Sci U S A, 113, 4176 - 4181
Crystal Structure of the Herpesvirus Nuclear Egress Complex Provides Insights into Inner Nuclear Membrane Remodeling.
Zeev-Ben-Mordehai T. et al, (2015), Cell Rep, 13, 2645 - 2652
Structural Basis of Vesicle Formation at the Inner Nuclear Membrane.
Hagen C. et al, (2015), Cell, 163, 1692 - 1701
Extracellular vesicles: a platform for the structure determination of membrane proteins by Cryo-EM.
Zeev-Ben-Mordehai T. et al, (2014), Structure, 22, 1687 - 1692
The full-length cell-cell fusogen EFF-1 is monomeric and upright on the membrane.
Zeev-Ben-Mordehai T. et al, (2014), Nat Commun, 5