CMU Computer Simulation Shows How Dynamin Releases Vesicles from the Cell Membrane

A computer simulation developed by biological physicists at Carnegie Mellon University has determined how the protein dynamin works with the cell membrane to bring important molecules into the cell. Their findings, published in eLife, can be used to better study the role the process plays in dynamin-related diseases like Charcot-Marie-Tooth disease and other neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and Alzheimer’s, Parkinson’s and Huntington’s diseases.

The cell membrane is a fortress of lipid molecules that separate the cell’s interior from its environment. The membrane has the important job of determining what molecules should be allowed into the cell — such as molecules that regulate protein processing, energy production and the immune response — and bringing those molecules into the cell’s interior.

When this process doesn’t work, vital molecules are stopped at the membrane and are unable to perform their job in the cell. For instance, in the case of Charcot-Marie-Tooth disease, mutations in dynamin have been shown to impair a variety of vital functions in nerve cells, such as cytoskeleton organization, autophagy and mitochondrial remodeling, even though the cause of the disease is still not fully understood.

One way that the lipid membrane can bring molecules into the cell is through dynamin driven membrane fission. In this process, the cell membrane envelops the molecule and creates a membrane bud that it draws into the cell’s interior. A spiral made from connected dynamin proteins wraps itself around the neck of the bud, pinching it off from the membrane and creating a vesicle that is free to enter the cell. Exactly how this fission happens is unknown.

“Dynamin’s structure is remarkably well-known,” said Carnegie Mellon Physics Professor Markus Deserno, who led the study. “And yet, its actual mode of operation has been ardently debated ever since it was first discovered more than two decades ago.”

While dynamin’s structure could be established using crystallography and electron microscopy, the structure of the membrane is much more difficult to resolve. The membrane’s lipids and proteins are complex and constantly in motion, frequently rearranging their tens of thousands of molecules to complete the tasks necessary for a cell to function and survive. 

Carnegie Mellon biological physicists, including Deserno, have created some of the most effective computer simulations of a lipid membrane. These allow researchers to see, often for the first time, what happens at the cell membrane under predetermined conditions.

In eLife, Deserno and former Carnegie Mellon postdoctoral researcher Martina Pannuzzo and graduate student Zachary A. McDargh detail a computational model that simulates the geometry and elasticity of the lipid membrane and dynamin. They used the model to test three theories about how dynamin acts to separate a vesicle from the membrane: constriction, where dynamin simply pinches off the vesicle; elongation and constriction, where dynamin stretches the membrane neck in order to trigger pinching-off of the vesicle; and constriction and rotation, where dynamin additionally twirls its filament to create torques that help detach the vesicle.

Their simulation showed that twirling was the most efficient method for membrane fission, while elongation actually reduced efficiency. Furthermore, the twirling process showed changes in the dynamin molecules that resembled those seen in previous experiments. 

“Our findings offer a detailed biophysical assessment of how dynamin’s geometry, elasticity, molecular interactions and expenditure of chemical energy work together to drive membrane fission — or how this might fail in several dynamin-related diseases,” said Deserno.

In addition to using the model to study disease, Deserno hopes that the model’s concept can be transferred to other membrane remodeling enzymes that are poorly understood, like the ESCRT-III complex, which plays a role in neurological disorders and the transmission of viruses between cells.

The research was funded by the National Science Foundation (1464926, 1764257), a Carnegie Mellon University Mellon College of Science/College of Engineering Postdoctoral Fellowship and the European Union’s Horizon 2020 research and innovation program under a Marie Sklodowska-Curie grant (754490).