Our skin and tissues act as a defense against the outside world, serving as barriers to prevent unwanted substances from entering our bodies. These protective barriers need to be securely fastened, which is where tight junctions come into play. The formation of these tight junctions has puzzled scientists for a long time. However, an interdisciplinary research team led by Prof. Alf Honigmann at the Biotechnology Center (BIOTEC) of Dresden University of Technology has recently discovered that these vital proteins create a liquid-like substance on the surface of cells, similar to the water droplets that form on a cold window. Their research findings were published in the journal Nature.
Our skin functions as a protective barrier against external threats and must be securely sealed to prevent breaches, much like a robust brick wall. Likewise, organs like the lungs and intestines require tight seals to ensure their contents do not leak into other areas of the body. The outer layers of these organs create these seals with specialized structures known as tight junctions.
Tight junctions can be likened to the spaces filled between floor or wall tiles. They form protective belts around the top of each cell, linking them to neighboring cells to establish a strong seal.
“In contrast to the stationary joints between tiles or the mortar in a brick wall, tight junctions are dynamic. Our skin and organs are soft and the cells continually change shape. Therefore, tight junctions must adapt to these changes while effectively sealing the gaps,” says Prof. Honigmann, who is a chair of Biophysics and leads a research team at the BIOTEC. “Understanding how tight junctions create such a resilient yet adaptable material around the cell edges has been an intriguing scientific challenge.”
Condensation on a Surface
To delve into the formation of these seals, Prof. Honigmann’s team utilized sophisticated biophysical techniques to observe this process in real-time. They devised a method to control the formation of tight junctions chemically, allowing them to switch it on and off at will. They also employed genetic engineering to tag the sealing proteins with a fluorescent marker, enabling them to use advanced microscopy techniques to watch tight junctions form as it happened.
Collaborating with theoretical physicists led by Frank Jülicher at the Max Planck Institute for Physics of Complex Systems (MPI-PKS) in Dresden, the team demonstrated that the self-assembly of tight junctions is driven by a physical phenomenon known as surface wetting.
“It is fascinating that these proteins exhibit behavior similar to that of water. By combining our observations with theoretical models, we essentially identified this process as analogous to the physical phenomenon of liquid condensation on surfaces,” explains Dr. Karina Pombo-Garcia, the lead researcher for the project and now a research group leader at the Rosalind Franklin Institute in England.
Tight junction proteins adhere to the cell membrane where cells come into contact. Once the number of bound proteins hits a certain level, they condense into a liquid that gradually forms into droplets on the cell surface. Eventually, these droplets elongate and merge to create a continuous belt around the cells, effectively sealing the spaces between them to make our skin and organs airtight.
“You may have seen tiny droplets of water form on a cold window during winter. It’s that same principle, but happening on a microscopic scale,” adds Dr. Pombo-Garcia.
Liquids Made of Proteins
As early as 2017, the Honigmann team suspected that tight junction proteins might behave like liquids. “We put in considerable effort to figure out how to measure and observe these liquid-like properties,” remarks Prof. Honigmann. “Luckily, we were positioned perfectly at the right time.”
The groundwork for this discovery was laid at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden, where researchers are pioneers in the field of condensate biology, a newly defined area of study centered on proteins that form large assemblies with liquid-like characteristics.
“Condensate biology is an exciting field as it helps connect different scales. One of the major challenges in biology is deciphering how structures like cell organelles arise from countless molecular interactions in the cytoplasm. We now know that certain biomolecules can self-organize into materials such as liquids and gels. This provides us the framework to apply well-known physical concepts like condensation and other phase transitions to explain structural formation in biology,” concludes Prof. Honigmann.
