It’s always rush hour inside the cell membrane, where molecular commuters crowd each other and get in each other’s way. One molecular commuter, however, won’t be slowed down. It’s the rhomboid protein. It has a sharp elbow, or fold, that distorts intramembrane lipids and thereby reduces local membrane viscosity. While the rhomboid protein may seem rude as it elbows past lipids, it is simply doing what many harried commuters must do if they are to minimize travel time.

In fact, rhomboid proteins hustle around the cell membrane twice as fast as they should, that is, twice as fast as a mathematical equation, the Saffman-Delbrück equation, would predict. The speedy progress of rhomboid proteins was noticed by researchers based at Johns Hopkins University School of Medicine. After the researchers labeled single rhomboid enzymes with chemicals that make them glow, the “gangway” behavior of the enzymes became clear.

The researchers, who were led by molecular biologist and geneticist Siniša Urban, PhD, proceeded to look at the enzymes more closely. They found that the enzymes interact with and change the shape of fats in the membrane as they move. The fats become less sticky, allowing the big protein to slip through.

Additional details of this work appeared February 1 in Science, in an article titled, “Rhomboid distorts lipids to break the viscosity-imposed speed limit of membrane diffusion.” In this article, the Johns Hopkins scientists noted that rhomboid enzymes are found in the cell membrane of almost every life form on Earth. Also, the scientists argued that the study of these enzymes could reveal targets for treating parasitic infections, cancer, inflammation, and neurodegeneration.

“Enzymes that cut proteins inside membranes regulate diverse cellular events, including cell signaling, homeostasis, and host-pathogen interactions,” wrote the article’s authors, who indicated that adaptations that enable catalysis in this exceptional environment are poorly understood.

“Hydrophobic mismatch with the irregularly shaped rhomboid fold distorted surrounding lipids and propelled rhomboid diffusion,” the authors continued. “The rate of substrate processing in living cells scaled with rhomboid diffusivity. Thus, intramembrane proteolysis is naturally diffusion-limited, but cells mitigate this constraint by using the rhomboid fold to overcome the ‘speed limit’ of membrane diffusion.”

Enzyme Warps Space to Break the Cell’s Speed Limit — Individual rhomboid proteins being tracked in a human cell. As researchers watched these proteins travel, they found that many were moving more quickly than they “should” be able to based on the known physics of the cell (traced in red). They found that the rhomboid protein’s unique shape allows it to warp its environment, allowing it to move quickly from one target to another. [Siniša Urban]

Why do some proteins need to move quickly? The researchers believe that rhomboid enzymes developed this ability so they could scour the membrane quickly, looking for targets to cut. Some of these targets must be released swiftly from the membrane to provide real-time signals to other cells that conditions have changed. Other enzymes in the membrane probably also need to hurry their search for targets. Understanding how this happens in the rhomboid protein will help scientists learn more about these proteins and their roles in disease.

The insights from the current study could have implications even beyond catalysis. “Some rhomboid proteins that lost their catalytic residues still play important roles in membrane biology,” the article’s authors explained. “Derlins, for example, facilitate endoplasmic reticulum (ER)–associated degradation of damaged proteins to safeguard the health of a cell. But without proteolytic activity, it has been difficult to rationalize their role. It is now tempting to speculate that Derlins disrupt local lipid interactions to help the Hrd1 channel translocate damaged proteins across the ER membrane.”

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