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Functional Analysis of Syntaxin4/Munc18c Interactions

Reference	BB/D000211/1
Principal Investigator / Supervisor	Professor Nia Bryant
Co-Investigators / Co-Supervisors	Professor Gwyn William Gould
Institution	University of Glasgow
Department	School of Life Sciences
Funding type	Research
Value (£)	239,276
Status	Completed
Type	Research Grant
Start date	01/11/2005
End date	31/10/2008
Duration	36 months

Abstract

Membrane traffic in all eukaryotic cells is controlled by the formation of specific SNARE complexes. Understanding the control of the formation of these complexes, spatially and temporally, represents an important research goal. The Sec1p/Munc18c (SM) family of proteins are involved in the control of membrane traffic in all eukaryotic cells likely through their interaction with the Syntaxin family of t-SNAREs. Although it is clear that SM proteins are essential for SNARE-dependent fusion, their mechanism of action remains controversial. SM family members share a high level of homology over their entire length, and structural studies have revealed that they all adopt the same arch-shaped structure indicating a common mode of action. However, the structures of two Syntaxin/SM protein complexes revealed distinct modes of interaction, hindering the formulation of unifying models for SM protein function. We contend that both modes of binding are utilised by all Syntaxin/SM pairs throughout the SNARE complex assembly/disassembly cycle. In this proposal, we shall directly test this hypothesis using the SM/Syntaxin pair involved in insulin-stimulated GLUT4 translocation (Munc18c/Syntaxin4). We will used a multidisciplinary approach to understand the regulation of this multi-protein complex assembly/disassembly. Our specific aims are therefore: To quantify the interaction(s) of Munc18c with Syntaxin4 (Sx4), in both monomeric and SNARE complexed states, and selectively perturb these interactions by mutagenesis. To define the functional consequences of the above perturbations both in vitro and in vivo.

Summary

One of the most important evolutionary changes that has occured is the development of intracellular compartments. All eukaryotic (plant and animal) cells contain many membrane-enclosed structures which provide the basis for intracellular specialisation. For example, in order to degrade unwanted components, cells contain degradative enzymes. It is vital that these are sequestered away from other cellular components to avoid destruction of valuable molecules. In addition, the cell has developed a complex assembly line of modifications that are added to proteins in a specific order as they travel to their final destination. This necessitates the accurate passage of molecules between compartments, a process known as vesicular transport. To control the network of vesicular transport steps between all the various intracellular compartments, it is necessary to use complex machinery to ensure that transport occurs between the appropriate compartments at the appropriate time. The goal of our research proposal is to understand, at the molecular level, the function of some of the molecules involved in this process.

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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