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University of Cambridge Conservation Research Institute



Transmembrane proteins are moved between organelles in transport vesicles,
a process that is essential for eukaryotic cells. Defects in vesicle trafficking pathways lead to a wide range of pathophysiological effects. We take a
combined structural and functional analyses approach to dissecting the
mechanisms that control this process.

Cargo is sorted into the curved membrane of a forming vesicle and once
membrane deformation is completed, the vesicle buds from the donor
membrane. Subsequently it is transported to and then fuses with its target
membrane. The protein coats that surround a transport vesicle possess
self-assembly, membrane deformation and cargo recognition functions.
Cargo selection is mediated by the direct binding of coat components to
determinants in the cytosolic portions of transmembrane cargo. In endocytic
clathrin-coated vesicles (CCVs), the most commonly used recognition
motif determinants are YxxΦ and ExxxLL, which are recognised by the
AP2 clathrin adaptor. Membrane deformation is achieved through a
combination of the insertion of helices into the membrane bilayer and
molecular crowding. In endocytic CCVs, the clathrin adaptor CALM plays
a central role in this process along with AP2 and membrane-sculpting
BAR-domain-containing proteins.

SNAREs are membrane-embedded proteins, which provide specificity and
energy to transport vesicle-organelle fusion events. Appropriate SNAREs must
be actively sorted into transport vesicles to allow the vesicles to fuse with
their desired target organelle and also to return SNAREs that are required
for subsequent vesicle transport events to their correct location. These
recognition events, which occur in parallel with standard cargo selection, are mainly mediated by direct and highly specific recognition of the folded
regions of SNAREs by vesicle coat components. In collaboration with other
groups in CIMR and elsewhere, we investigate the structures and functions
of proteins that control transport vesicle–organelle and organelle–organelle
fusion through regulating SNARE-mediated membrane fusion activity, SNARE
localization and membrane tethering events. One example of such a study
is our work on the SNARE VAMP7 and its binding partner the retromer-coat-associated protein VARP.


Professor of Structural and Molecular Biology