Membrane fusion a mystery no more

The findings appear in the current edition of the journal PLoS Biology.

"Within our cells, we have communicating compartments called vesicles (a bubble-like membrane structure that stores and transports cellular products)," said Dr. Christopher Peters, assistant professor of biochemistry and molecular biology at BCM and lead author on the study. "These vesicles migrate through the cell, meet other vesicles and fuse. That fusion process is, in part, mediated through SNARE proteins that bring the vesicles together. How this happens has been in question for years."

SNARE proteins

The classic model for this process has been studied using artificial liposome models created in a lab. Peters and his colleagues knew a more physiological fusion model had to be studied in order to see a more accurate account of exactly what acts on this process. Using purified yeast organelles they were able to see that more factors come into play than had been originally believed.

In the classic model, it was believed SNARE proteins originating from two opposing membranes are somehow activated and separated into single proteins. Accepter SNARE proteins then form, allowing fusion with another vesicle membrane. How this mechanistically happens has been unknown.

Tethering factor

"What we found with our physiological model is that a tethering complex (termed HOPS) is interacting with the SNARE proteins, activating them to begin this process. Also, the SNARE proteins do not completely separate into single proteins as first believed. Only one protein is detached, leaving behind the acceptor complex," Peters said. "This new acceptor SNARE-complex incorporates the single SNARE that has separated from another vesicle and the two vesicles are in position to fuse."

Researchers found that when this tethering factor was removed, the SNARE proteins were unstable and there was no fusion.

"This finding deals with one of the most fundamental reactions in a cell, how membranes fuse with each other. It is important to understand how this works, because when these events go wrong, either accelerating or slowing down, then it can affect certain disorders such as tumor formation," Peters said. "By using our physiological yeast fusion model, the impact of these tethering factors on the SNARE topology can be investigated, along with the many other factors that come into play. This was not the case in the artificial liposome models used in the past."

Others who contributed to the study include: Kannan Alpadi, Aditya Kulkarni and Sarita Namjoshi, all with the department of biochemistry at BCM; and Veronique Comte, Monique Reinhardt, Andrea Schmidt and Andreas Mayer, all with the department of biochemistry at the University of Lausanne, Switzerland.

Funding for this study came from the National Institutes of Health and Boehringer Ingelheim.