In clearest view ever of cell membrane, VCU team finds unexpected structure and new areas for pharmaceutical research

An illustration of a cell membrane.
An illustration of a cell membrane. (Getty)

For more information, contact Greg Weatherford, VCU School of Pharmacy, at goweatherfor@vcu.edu

Working with a Nobel Prize-winning biophysicist, a team of researchers at Virginia Commonwealth University has used an innovative technique to gain the clearest view yet of a patch of cell membrane and its components, revealing unexpected structures and opening up new possibilities for pharmaceutical research.

Cell membranes are formed largely of a bimolecular sheet, a fraction of the thickness of a soap bubble, in which two layers of lipid molecules are packed with their hydrophobic tails pointing inward and their hydrophilic heads outward, exposed to water.

The internal shape and structure of this lipid bilayer have remained largely mysterious after almost a century of research. This is in large part because most methods to examine membranes use detergents, which strip away the lipids that make up much of the membranes’ structures.

In a newly published paper in Proceedings of the National Academy of Sciences of the United States of America, the team — led by Youzhong Guo, Ph.D., of the Virginia Commonwealth University School of Pharmacy — used a new detergent-free method that allowed them to examine the membrane of an E. coli cell, with lipids still in place.

‘Surprising’ structure
Where earlier models had shown a fluid, almost structureless lipid layer — one often-cited research paper compared it to different weights of olive oil poured together — the VCU-led team was startled to find a distinct hexagonal structure inside the membrane. This has led the researchers to propose that the lipid layer might act as both sensor and energy transducer within a membrane protein transporter.

“The most surprising outcome is the high order with which lipid molecules are arranged, and the idea they might even cooperate in the functional cycle of the export channel,” said Joachim Frank, Ph.D., of Columbia University, a 2017 Nobel laureate in chemistry and coauthor of the paper. “It is counterintuitive since we have learned that lipids are fluid and disordered in the membrane.”

Photo of Youzhou Guo
Guo

The researchers were able to get such a clear view because they used an innovative method to isolate and stabilize the membranes. Employing poly-styrene-maleic-acid to break cell membrane into nanoparticles that were then isolated and captured in a layer of sophisticated polymer, the researchers used the state-of-the-art cryo-electron microscope at New York Structural Biology Center (NYSBC) to get a clear look at the lipid bilayer.

“Being able to pull proteins out of cell membranes without using detergents to break up the lipid bilayers truly is a fantastic advance,” said Wayne Hendrickson, Ph.D., a university professor at Columbia, scientific director of NYSBC and coauthor of the paper.

The technique and its revelations could have significant pharmaceutical value, added VCU’s Guo. He pointed out that about half of medical drugs target the cell membrane, and proposed that improved understanding of their layers of lipids and proteins could lead to new or more-effective therapies.

The authors of the paper, “Structure and Activity of Lipid Bilayer Within a Membrane Protein Transporter,” are Weihua Qiu, Guoyan G. Xu, Yan Zhang and Youzhong Guo, of Virginia Commonwealth University, and Ziao Fu, Robert A. Grassucci, Joachim Frank and Wayne A. Hendrickson of Columbia University.

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