I am investigating the molecular mechanisms underlying regulated membrane fusion and endocytic retrieval of vesicular membrane and proteins. Although many of the proteins invovled in the delivery of cargo -laden vesicles to the plasma membrane, and their subsequent fusion, have been identified, the molecular events driving membrane fusion and how this process is regulated is largely unknown.

Perhaps the most highly regulated form of membrane fusion occurs in neuronal communication. Neurons communicate with each other or effector organs (in the case of the illustration to the left with skeletal muscle) through the release of small synaptic vesicles loaded with neurotransmitters. This release occurs in response to an action potential which results in calcium influx into the presynaptic terminal triggering membrane fusion and the release of neurotransmitters.

The general scheme for this process, and the subsequent retrieval of phospholipid membrane and vesicular components is depicted in the diagram to the left. Tight spatial and temporal control of this process is essential for the normal physiological funtioning of neurotransmission.

The proteins believed to provide the driving force to overcome the large energetic barrier for the fusion of two phospholipid bilayers are the SNAREs.

Rickman, C., Jimenez, J.L., Graham, M.E., Archer, D.A., Soloviev, M., Burgoyne, R.D. and Davletov, B. (2005) Conserved prefusion protein assembly in regulated exocytosis. Mol Biol Cell, x(xx), xxxx-xxxx. [PubMed]

Rickman, C. and Davletov, B. (2005) Arachidonic acid allows SNARE complex formation in the presence of Munc18. Chem Biol, 12(5), 545-553. [PubMed]

Rickman, C., Archer, D.A., Meunier, F.A., Craxton, M., Fukuda, M., Burgoyne, R.D. and Davletov, B. (2004) Synaptotagmin interaction with the syntaxin/SNAP-25 dimer is mediated by an evolutionarily conserved motif and is sensitive to inositol hexakisphosphate. J Biol Chem, 279, 12574-12579. [PubMed]

Rickman, C., Craxton, M., Osborne, S. and Davletov, B. (2004) Comparative analysis of tandem C2 domains from the mammalian synaptotagmin family. Biochem J, 378, 681-686. [PubMed]

Rickman, C.*, Meunier, F.A.*, Binz, T. and Davletov, B. (2004) High affinity interaction of syntaxin and SNAP-25 on the plasma membrane is abolished by botulinum toxin E. J Biol Chem, 279, 644-651. [PubMed]

Rickman, C. and Davletov, B. (2003) Mechanism of calcium-independent synaptotagmin binding to target SNAREs. J Biol Chem, 278, 5501-5504. [PubMed]

Hu, K., Carroll, J., Fedorovich, S., Rickman, C., Sukhodub, A. and Davletov, B. (2002) Vesicular restriction of synaptobrevin suggests a role for calcium in membrane fusion. Nature, 415, 646-650. [PubMed]