Reveal how protein degeneration causes genetic diseases

of individual building blocks in proteins is the cause of many genetic diseases, but it is still largely unknown how this repetition actually causes the disease. Researchers in Berlin studied how repeated extensions cause the disease and found that the attraction between mutant proteins causes them to alter the behavior of tiny droplets in cells. This pattern of action can explain many other genetic diseases.Each hand has five fingers and each foot has five toes -- the whole symmetry of our body is controlled by the HOX gene during development. This set of genes is essential for the structure of a developing embryo along the axis of the body.For example, defects in the HOXD13 gene can lead to finger excess and fusion, a developmental disorder known as toe-toe malformation. The molecular processes that cause the disease are not known until now.The team, led by Denis Hnisz and Daniel Ibrahim of the Max Planck Institute for Molecular Genetics in Berlin, found that the mutation led to the production of proteins with altered chemical properties. The HOXD13 protein, along with other molecules, forms tiny droplets called coagulants, but the composition of the droplets changes, so the protein's regulatory function is impaired. The scientists report in the scientific journal Cell that changes in the composition of this gene-driven condensed matter may be a new mechanism for a potential genetic disease.Protein droplets beat randombut why do proteins accumulate in droplets? "In salad dressings, vinegar forms small droplets in the oil, and certain molecules in the cells bind in a similar way to form protein droplets, called condensed matter," said Denis Hnisz, one of the study's senior authors. Because of their chemical properties, molecules attract each other and are separated from the environment.There are practical reasons for this phenomenon, Hnisz said. "To read a gene, cells need 300 to 500 proteins. If this huge machine had to be assembled completely by accident at the right time and place, it would take about 10 billion years -- in other words, it would never be assembled. "That's why cells bundle key molecules needed to accomplish a particular task into small, droplet-like packages.Gravity determines the composition of dropletsmolecules like THEX proteins are made up of different fragments, some of which have relatively hard three-dimensional structures, while others, known as "inner disordered areas," are soft and fluffy. "These molecular tails protrude out of proteins like cooked noodles, " says Hnisz. "We believe they are critical to the formation of cell cohesion."The tail of HOXD13 contains a large row of alanine. "In patients with cogeneration, the alanine tail expands from 15 residuals in a healthy sequence to at least seven other residues," said Daniel Ibrahim, a developmental biologist who specializes in genetically-caused bone malformations. The HOXD13 mutation in cogeneration was first reported in 1996 by geneticist Stefan Mundlos, who currently works at MPIMG, but the molecular mechanisms of the disease remain a mystery.The altered molecules have different behaviorsTo study how the tail extension of HOXD13 affects the function of the protein, Shaun Basu, one of the study's two lead authors, first mixed hoxD13 molecules of different lengths with other proteins to understand the function of HOXD13. The modified protein removes the binding from the droplets -- the longer the tail, the more obvious the effect. The researchers, in collaboration with colleagues at the Free University of Berlin, showed this behavior in cells using a high-resolution microscope.But will changes in cell coagulation components affect the function of HOXD13? "We examined embryos from mice with the extended HOXD13 gene, who, like human patients, developed toe-to-toe malformations," Ibrahim said. In these embryos, the composition of the coagulants in the cells of mice with toe-to-toe malformations was different from that of mice that had not been genetically modified. There are fewer inter-finger cells in limb buds, and inter-finger cells usually occupy space between fingers and then disappear. Basu said: "The composition of the condensed matter of mutated cells can be changed by chemical mixtures, just like drugs. I think this is a really fascinating opportunity for us to eliminate pathological symptoms in the future by understanding the mechanisms of the disease. Howmechanisms associated with other diseases HOXD13 is not the only protein with a molecular tail that affects its behavior and function in condensed matter. Computational biologist Sebastian D. Mackowiak, who led the study, and Shaun Basu analyzed another 1,500 human gene regulatory proteins with molecular tails and were able to identify seven tails with different chemical properties. About 300 gene-regulating proteins, such as HOXD13, have high levels of alanine in their tails. The researchers then changed the amount of alanine residues in some of these proteins, finding that the changes led to changes in the composition of the condensate and hindered the function of the proteins in the cells.The work was a victory forHnisz and his colleagues. Microscopists first described condensed matter in the form of small cell balls decades ago, but until recently their functionality was questioned by many. "The fact that condensation is directly related to the development of disease can no longer be denied," Hnisz said. It is absolutely reasonable that many other diseases may also be caused by changes in the composition of cell coagulants. (Bio Valley Bioon.com)