Membrane Curves Make the Difference in Capturing Proteins-Mellon College of Science - Carnegie Mellon University

Tuesday, June 5, 2007

Membrane Curves Make the Difference in Capturing Proteins

Findings Reported by Carnegie Mellon-bound biophysicist Markus Deserno

To go about its work, a cell constantly remodels its fluid membranes. Its outer membrane is chock full of proteins for various tasks, such as recognizing other cells, getting nutrients or creating channels that generate electric current. This membrane routinely captures molecules from its environment, encapsulates them in bits of membrane, and sends its cargo to the interior for processing. Inside a cell, other membranous structures like the endoplasmic reticulum also curve around proteins and bud to form “vesicles.” Proteins enclosed within such vesicles are transported to different locations inside cells to prevent them from getting mixed up along the way with other substances. Without this generic ability to curve its protein-studded membranes and bud off cargo shuttles — a process called vesiculation — a cell couldn’t survive.

Proteins involved in vesiculation — called remodeling proteins — essentially make membranes curve. Ultimately, a cell membrane somehow curves and proteins coalesce into pockets that separate from the main membrane. But elaborating the dynamics of vesiculation has proven vexing until now, according to Markus Deserno, a molecular biophysicist with the Max Plank Institute for Polymer Research in Mainz, Germany. Current theories and experiments are limited in their ability to resolve whether aggregating proteins physically repel or attract one another, according to Deserno, who is joining the Physics Department at Carnegie Mellon University this fall. Cell experiments don’t provide detailed information about nanoscale geometric changes, and theoretical approaches of cell membrane dynamics require imperfect calculations.

Now, a computer simulation developed by Deserno’s team at Max Planck reveals the physical mechanism that enables this phenomenon and resolves differences between experiment and theory. The results, reported in the May 24 issue of Nature, shows that membrane curvature results in attraction between remodeling proteins. The results show the biophysical foundation for how vesiculation takes place.

“Ultimately, understanding the dynamics of vesiculation is key to advancing the design of anti-viral therapies or understanding how protein processing goes awry within a cell and leads to disease,” said Deserno, who plans to expand this research when he joins Carnegie Mellon’s Physics Department in fall 2007.

At Max Planck, Deserno’s team created a computer simulation of cell membrane with a lipid bilayer — a soap-like film made of 50,000 individual lipids molecules — and studded it with 36 evenly spaced balls representing remodeling proteins. Then he set the simulation to allow the fluid membrane to fluctuate as it normally would.

During the simulation, the artificial membrane began curving in places. In creating curved membrane structures, each ball bent the membrane a little bit. This local curvature spread around a ball like a little “halo”. When two balls approached one another, the overlapping halos led to an indirect interaction. Thus, while there was no explicit interaction between the balls, these objects indirectly attracted each other via the membrane, Deserno’s group found.

“With this work, we provide solid support for a mechanism that has been gaining in popularity recently,” Deserno said. “To date, no one has demonstrated at the biophysical level exactly what everybody seemed to expect -- that remodeling proteins aggregated to facilitate vesiculation. This simulation shows us that proteins need not interact directly to drive critical process.”

Understanding how vesiculation physically operates should make it easier in the long run to rationally design and deliver drugs to individual cells, according to Deserno. “This is the biggest practical value of our research. Now that we have a proposed mechanism, we can subject it to well-posed questions, such as why certain proteins are always present during vesiculation.”

“Deserno’s cover story in Nature re-enforces our excitement in hiring Markus,” said Fred Gilman, head of the Department of Physics at the Mellon College of Science. “Already, Markus is playing an important role in our biological physics initiative.”

At Carnegie Mellon, Deserno will collaborate with the Pittsburgh Supercomputing Center, faculty from various Carnegie Mellon departments and colleagues from outside universities.

“Computer simulations of cell membrane dynamics are critical to complementing experimental techniques and driving this field forward.”

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By: Lauren Ward