Cambridge Institute for Medical Research

Professor David Owen

Professor David Owen

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Structural Biology of Transport Vesicle and Organelle Biogenesis

Transmembrane proteins are moved between organelles in transport vesicles.  Once cargo has been sorted into a forming vesicle, the vesicle buds from the donor membrane and is then transported to and fuses with the target membrane. The protein coats that surround transport vesicle possess both a self-assembly function, which results in polymeric lattice formation and a cargo recognition function.  The latter is mediated by the direct binding of coat components to determinants in the cytosolic portions of trans-membrane cargo, most commonly used being short linear motifs.  In clathrin-coated vesicles (CCVs) the most commonly used motifs are recognised by clathrin adaptors : YxxF and ExxxLL recognised by AP complexes, FxNPxY recognised by PTB containing proteins and poly-ubiquitination modifications recognised by epsins and GGAs.  SNAREs are membrane-embedded proteins, which provide specificity and energy to transport vesicle:organelle fusion events.  Appropriate SNAREs must also 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. In CCV-mediated transport we have elucidated the molecular mechanisms by which a variety of SNAREs (Vti1b, VAMP7, VAMPs3&8) are transported by the clathrin adaptors (epsinR, Hrb and CALM) respectively.  Vesicle coat components as well as proteins that control transport vesicle:organelle and organelle:organelle fusion through SNARE regulation and membrane tethering are recruited to appropriate membranes through their binding to membrane-inserted small G-proteins and membrane phospholipids as well as by their interactions with various trans-membrane proteins.

In collaboration with various groups both within and outside the CIMR we are taking an integrated structural/functional approach to studying such interactions from a number of transport vesicle and organelle biogenesis events.

 

Funding

  • The Wellcome Trust

Group Members

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Lauren Jackson
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Bernard Kelly
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Sharon Miller
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Richard Suckling
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Antoni Wrobel