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Our bodies are protected from external factors by tissue barriers, such as the skin. It is crucial for these barriers to be securely sealed to prevent the entry of undesirable substances. This sealing is accomplished through structures known as tight junctions. However, the mechanisms behind the formation of these junctions have remained largely unclear until now. A multidisciplinary team of researchers, led by Prof. Alf Honigmann at the Biotechnology Center (BIOTEC) of Dresden University of Technology, has recently revealed that the proteins responsible for creating these seals behave similarly to a liquid, akin to water droplets on a cold surface. Their research findings are detailed in the journal Nature.
The skin serves as a vital defense against environmental threats and, much like a sturdy wall, requires diligent sealing to remain intact. Likewise, vital organs such as the lungs and intestines must employ tight seals to ensure their contents do not leak into other areas of the body. The outermost layer of these organs facilitates this protection through specialized intercellular connections known as tight junctions.
Tight junctions can be likened to the joints found between tiles on a floor, functioning as belts that encircle the upper portions of cells and connect them to their neighbors in order to create a secure seal.
“In contrast to the static nature of tile joints or the mortar in brick walls, tight junctions are dynamic entities. Since our skin and organs consist of soft tissues, the cells are constantly changing shape. Thus, tight junctions must possess the ability to shift and adapt while still maintaining a robust seal,” explains Prof. Honigmann, who holds a chair in Biophysics and leads a research group at the BIOTEC. “Determining how tight junctions could create such a resilient yet adaptable material around the cell perimeter has been an exciting scientific challenge.”
Condensation on a Surface
To investigate the formation of these seals, Prof. Honigmann’s team employed sophisticated biophysical techniques allowing them to monitor the process in real-time. They engineered a method to chemically modulate the formation of tight junctions and tagged the sealing proteins with fluorescent markers to visualize their dynamics through high-resolution microscopy.
Collaborating with theoretical physicists, led by Frank Jülicher from the Max Planck Institute for Physics of Complex Systems (MPI-PKS) in Dresden, the research team was able to demonstrate that the self-assembly of tight junctions is influenced by a physical process known as surface wetting.
“It is captivating how these tight junction proteins mimic the behavior of liquids. By integrating our experimental observations with theoretical models, we uncovered a process akin to condensation on a surface,” states Dr. Karina Pombo-Garcia, a key researcher in the project and currently leading her own research group at the Rosalind Franklin Institute in England.
Tight junction proteins attach themselves to the cell membrane at points where adjacent cells meet. Once the quantity of binding proteins surpasses a specific threshold, they condense into a liquid droplet on the cell surface. These droplets eventually merge and elongate, forming a continuous belt around the cells and effectively sealing the intercellular spaces, thus creating an airtight barrier that protects our skin and organs.
“It’s reminiscent of how tiny droplets form on a cold window during winter. This phenomenon operates on a molecular scale,” Dr. Pombo-Garcia adds.
Liquids Made of Proteins
The Honigmann team began to hypothesize the liquid-like behavior of tight junction proteins as early as 2017. “We dedicated considerable effort to measure and identify these properties,” notes Prof. Honigmann. “Fortunately, we found ourselves in the right environment with the necessary resources.”
The groundwork leading to this groundbreaking discovery was laid at the Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG) in Dresden. This institute is recognized as a leader in the field of condensate biology, which investigates how proteins can assemble into large, liquid-like structures.
“Condensate biology presents exciting possibilities, as it bridges various scales in biological research. A persistent challenge in biology is understanding how larger structures like cellular organelles emerge from countless molecular interactions in the cytoplasm. We are now aware that certain biomolecules can organize themselves into materials like liquids and gels, allowing for the application of well-established physical principles such as condensation and other phase transitions to elucidate structural formation in biology,” concludes Prof. Honigmann.
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