For Release: August 14, 2007
Contact: DMS Communications 603-650-1492
Tipping Point for Cell Membrane Fusion: DMS Research Shows Delicate Balance for Coupling versus Breakup
HANOVER, NH—The merger of membrane "walls" separating components inside the cell is essential for sorting and moving proteins to their correct locations. Now DMS biochemists have determined a tipping point for that fusion, a key process for cell development and function. Their research, published this week (August 13-17) in the online Early Edition of PNAS (Proceedings of the National Academy of Sciences), offers further understanding of what guides the interactions among biological membranes.
A protein complex called SNAREs drives fusion. It brings membranes together and also stresses them as they bump against each other. Surface layers begin to disintegrate, but other proteins and lipids on each membrane are also needed for fusion to proceed without leaks or breaks.
A team led by Dr. William Wickner, professor of biochemistry, found that the precise abundance of SNARE proteins is crucial to the balance of membrane fusion, regulating whether the SNARE proteins trigger a successful union or lead to a disastrous breakage (lysis) of cell membranes. Knowing what controls fusion among membranes of cell components can help open new avenues for modulating the process for possible disease treatment or prevention.
"Membranes fuse at each step of cell growth, hormone secretion and neurotransmission. This fusion is central to all biology and medicine," Wickner said. "However fusion and lysis are closely related and we are only beginning to understand how cell organelles avoid lysis while allowing regulated fusion."
Using yeast, the researchers followed fusion and lysis in a cell organelle called the vacuole. A model for biochemical and genetic studies, yeast uses the same membrane fusion mechanisms as higher life forms.
The group engineered yeast to overproduce the four SNARE proteins that form a complex which promotes both the fusion and lysis of yeast vacuoles. By controlling the levels of SNAREs and other required proteins—including those from the Rab family—on the vacuole surfaces, they could measure the properties of fusing vacuoles.
Yeast membranes with high levels of SNAREs fused without the normally required Rab proteins. However, this streamlined process often ruptured the vacuoles, the investigators found. When the Rab proteins were present, much smaller amounts of SNAREs were required and fewer vacuoles split, indicating that Rab proteins are essential for maintaining the integrity of vacuoles during fusion.
"Instead of just making more SNAREs to promote fusion, nature uses Rabs to channel membrane stress exclusively to fusion. A focus of future research will be to try to understand how Rabs and their related effectors achieve this," Wickner added.
The results support the notion of SNARE proteins as "powerful but hapless." They are "indeed the motor of membrane fusion, driving the energetics of the reaction, but.... unable to channel the energy released by their complex formation, and need to be organized," wrote University of Texas biochemist Dr. Thomas Sudhof in an accompanying commentary.
Co-authors of the research are Vincent Starai, a postdoctoral fellow, and Youngsoo Jun, a recent graduate of the DMS molecular and cell biology program.