Our bodies and organs are protected from the external environment by tissue barriers such as the skin. These barriers must be properly sealed to prevent unwanted substances from entering. This seal is achieved through structures called tight junctions. However, how these tight intersections arise has long been a mystery. Now an interdisciplinary team of researchers, led by Prof. Alf Honigmann from the Biotechnology Center (BIOTEC) of the Technical University of Dresden, has discovered that the proteins responsible for these seals form a liquid-like material on the cell surface, similar to water. that condenses on a cold window. Their findings were published in the journal Nature.
Our skin acts as a protective shield against the outside world, and like a well-built brick wall, it must be properly sealed to prevent cracking. Likewise, our organs such as lungs or intestines need to be sealed to ensure that their contents do not pass into other body compartments. The outer layer of our organs achieves this with specialized seals between the cells known as tight junctions.
Close joints are much like a joint between floor or wall tiles. They are belts that surround the top of each cell and attach to the adjacent cells to form a tight seal between them.
“Unlike the joint between the tiles or mortar in the brick wall, tight intersections are dynamic. Our skin or organs are soft and the cells are constantly changing shape. Tight junctions must be able to adapt to cell shape changes and still be able to close the gaps,” explains Prof. Honigmann, Chairman of Biophysics and research group leader at BIOTEC. “How tight junctions can form such a robust yet flexible material around the cell perimeter has been an intriguing scientific question.”
Condensation on a surface
To understand how these seals form, Prof. Honigmann’s team used advanced biophysical methods to observe the process in real time. They developed a way to chemically switch the formation of tight junctions on and off at will. They also used genetic engineering to label the seal proteins with a fluorescent marker. Together, this allowed them to use high-resolution microscopy to see how tight junctions formed in real time.
Working with theoretical physicists led by Frank Jülicher from the Max Planck Institute for Physics of Complex Systems (MPI-PKS) in Dresden, the group was able to demonstrate that self-assembly of tight junctions is driven by a physical phenomenon called surface wetting.
“It’s fascinating that these tight junction proteins behave in a very similar way to water. By putting together our observations and the theoretical physics models, we arrived at what is essentially the physical process of liquid condensation on a surface ” says Dr. Karina Pombo -Garcia, the researcher behind the project and now research group leader at the Rosalind Franklin Institute in England.
Tight junction proteins bind to the surface of the cell membrane at the interface where the cells touch each other. When the number of proteins bound there reaches a certain threshold, the proteins condense into a liquid that gradually grows into a kind of droplet on the cell surface. Eventually, these droplets lengthen and touch each other, creating a uniform band around the cells. In this way, tight junctions close the spaces between cells to make our skin and organs airtight.
“Maybe everyone has seen it in the winter. Tiny droplets of water appear on a cold window. It’s exactly that, but on a molecular scale,” adds Dr. Pombo-Garcia.
Liquids made from proteins
As early as 2017, the Honigmann team began to suspect that tight junction proteins might behave like liquids. “We put a lot of effort into figuring out how to measure and observe these liquid-like properties,” says Prof. Honigmann. “Luckily we were in the right place at the right time.”
The early work leading to this discovery was conducted at the Max Planck Institute for Molecular Cell Biology and Genetics (MPI-CBG) in Dresden. Researchers at MPI-CBG are pioneers in the field of condensate biology, the newly discovered branch of biology that focuses on proteins that form large assemblies with liquid-like properties.
‘Condensate biology is a promising field because it bridges the gap between scale levels. One of the common problems in biology is understanding how structures such as cell organelles arise from the myriad molecular interactions in the cytoplasm. We now know that certain biomolecules can self-organize into materials such as liquids and gels. This allows us to adapt well-understood physical concepts such as condensation and other phase transitions to describe structure formation in biology,” concludes Prof. Honigmann.
