Studies Reveal Why Some Proteins “Flock Together”

SMN is concentrated in the Cajal body (left, red) of the nucleus (blue) of human cells. When SMN phosphorylation is inhibited, the concentration decreases and the Cajal body disappears.Credit: AG Gruss / University of Bonn

Almost every cell in our body contains a nucleus: a slightly spherical structure that is separated from the rest of the cell by a membrane. Each nucleus contains all the genetic information of humans. It acts as a kind of library, but with strict requirements. When a cell requires a protein-building procedure, it does more than just borrow the original information. Instead, the transcript is created in Nucleus.

The mechanism required for this is very complex. Especially because the transcript is not a simple copy. In addition to the essential information, the gene also contains many sections of meaningless “garbage”. When the transcripts are created, they are deleted. Biologists call this editorial revision “splicing.”

“A key role in splicing is played by the SMN complex, a“ molecular machine ”of nine different proteins,” explains Dr. Oliver Gruth of the University of Bonn Institute of Genetics. Life and health, an interdisciplinary research area of ​​the university. “Interestingly, these machines are not evenly distributed in the nucleus. Instead, they accumulate in a specific location called the Cajal body.” However, they transport the SMN complex to the cell nucleus that carries it to the Cajal body. There is no mechanism. Instead, the SMN proteins themselves have specific properties that are involved in their aggregation. It was previously unknown which of these was exactly.

The SMN complex has an unusually large number of phosphate groups

SMN complexes have distinctive features: they carry an unusually large number Phosphate group, A small molecule residue with a phosphorus atom in the center. “I suspected that this phosphorylation would promote massive clustering into the Cajal body,” explains Dr. Maximilian Schilling, a research group working with Oliver Gruth.

Phosphate groups are not part of the actual blueprint for proteins. It can be added later and removed again. This is often the way cells regulate the activity of their respective proteins. Phosphate groups are bound by a specific enzyme, kinase, in this process. “We have now individually inhibited each of the hundreds of human kinases and investigated how they affect the formation of the Cajal body,” says Schilling.

In this way, they encountered a network of kinases, and when they were blocked, the Cajal body disappeared significantly. Further analysis showed that in the absence of these kinases, phosphorylation of the SMN complex at specific sites was sharply reduced. This will stop the flash mob in the nucleus. The Cajal body collapses. This finding is particularly interesting because the identified kinases not only regulate splicing, but also the translation of such edited gene transcripts into proteins. Therefore, these are essential enzymes for the various steps of this important process.

Mutations cause serious illness

The SMN complex is known to human geneticists as well as its role in splicing. Individual mutations in that blueprint cause serious illness. Spinal muscular atrophyTo those who are affected. About 1 in 6,000 newborns are born with this genetic defect. Treatment is very expensive. The cost per patient can reach millions. “Some of the genetic defects that cause spinal muscular atrophy are near the phosphorylation site of the SMN complex,” Gruss explains. “Therefore, affected individuals may impair the attachment of phosphate groups to these sites and, as a result, also impair the formation of the Cajal body. This impairs splicing and then the symptoms of the disease. Is expected to occur. “

Therefore, the identified kinases may also be a good starting point for new therapies.Preliminary results from mouse model cells of human spinal muscular atrophy show that increasing drugs Kinase Activities also improve Cajal body Formation. “It’s completely unclear whether these drugs will also improve the pathological changes in complex organisms,” Gruss warns against rising expectations. “Therefore, it is still speculation at this stage that new treatment options will eventually emerge.”

Mathematical model reveals behavior of cellular enzymes

For more information:
Maximilian Schilling et al, TOR signaling regulates liquid phase separation of the SMN complex that governs snRNP biosynthesis. Cell report (2021). DOI: 10.1016 / j.celrep.2021.109277

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University of Bonn

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