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New discovery in living cell signaling
Date:7/3/2014

first specific genetic alterations linked to human cancers and it is now estimated that nearly a third of all human cancers can be traced to something going wrong with Ras activation. Defective Ras signaling has also been cited as a contributing factor to other diseases, including diabetes and immunological and inflammatory disorders. Despite this long history of recognized association with cancers and other diseases, Ras proteins have been dubbed "un-druggable," largely because their activation mechanism has been poorly understood.

A roadblock to understanding Ras signaling is that the membranes to which Ras proteins are anchored play a major role in their activation through SOS exchange factors. SOS activity in turn was believed to be allosterically regulated through protein and membrane interactions, but this was deduced from cell biological studies rather than direct observations. For a better understanding of how Ras activation by SOS is regulated, scientists need to observe individual SOS molecules interacting with Ras in a membrane environment. However, membrane environments have traditionally presented a stiff experimental challenge.

Groves and his research group overcame this challenge with the development of supported membrane arrays constructed out of lipid layers embedded with fixed patterns of metal nanostructures and assembled onto a silica substrate. The metal structures allow for the controlled spacing of proteins and other cellular molecules placed on the membranes. This makes it possible for the membranes to serve as a platform for assays that can be used to observe in real-time the activity of single molecules.

"In this case, our supported membrane allowed us to corral individual SOS molecules into nanofabricated patches that trapped all the membrane-associated Ras molecules they activated," Groves says. "This in turn allowed us to monitor the individual contribution of every molecule in the ensemble and reveal how the
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Contact: Lynn Yarris
lcyarris@lbl.gov
510-486-5375
DOE/Lawrence Berkeley National Laboratory
Source:Eurekalert  

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