Structure of the Munc18c protein involved in insulin-stimulated glucose transport

Institute for Molecular Bioscience, University of Queensland* Garvan Medical Research Institute**
â—‹Jennifer L Martin* Shu-Hong Hu* Catherine F Latham* Christine L Gee* Michelle Christie* Fred Meunier* David E James**

Membrane trafficking is an essential and regulated process that ensures cellular cargo is delivered to the correct destination in response to the appropriate stimuli. Docking and fusion of target and acceptor membranes are mediated by the formation of SNARE complexes between molecules on both membranes. Regulation of SNARE complex formation is vital and the process is subject to multiple levels of control. Members of the Sec1p/Munc18 (SM) protein family have been implicated in every SNARE-mediated membrane fusion step characterised to date and are thought to tightly control SNARE complex formation. Different SM proteins have been shown to interact with SNAREs via different mechanisms leading to the conclusion that their function has diverged.
We have examined the molecular interactions between Munc18c and its cognate SNARE. These molecules are ubiquitously expressed in mammals and are responsible for plasma membrane vesicle trafficking in muscle and fat cells of the GLUT4 glucose transporter in response to insulin signalling. This system is disrupted in Type II diabetes. Intriguingly Munc18c displays a SNARE binding pattern similar to that described for most other models of SM/SNARE interactions but significantly different to the binding pattern described for its closest relative mammalian Munc18a, that regulates neurotransmitter vesicle trafficking. Here we describe the 3.1A resolution crystal structure of Munc18c bound to a Syntaxin4 peptide.