Scientists from Moscow State University have determined the structure of the protein involved in leprechaun face syndrome


Employees at Moscow State University, along with colleagues, have determined the structure of a protein that is missing in patients with Williams syndrome, a serious human genetic disease known as leprechaun face syndrome. The study will help to identify the relationship between the lack of the studied protein and the manifestation of the symptoms of the disease. Results of the work published in the journal Frontiers in Molecular Biosciences, the study was supported by grants from the Russian Science Foundation (project no. 21-64-00006 and 20-04-00736) and the Russian Foundation for Basic Research (project no. 20-04-) . 00318).

Williams syndrome was first described by the New Zealand cardiologist John Williams in the middle of the 20th century: he noted that patients with similar defects in the cardiovascular system often have certain appearance characteristics. These features evoked a resemblance to the faces of elves in English book miniatures, so the disease received its second name, and even the patients themselves are considered a hypothetical prototype of the image of elves in English mythology. In addition to the “elfin” appearance, patients with Williams syndrome are characterized by extraordinary friendliness, kindness and responsiveness. All this manifests itself in the context of mental retardation.

This syndrome occurs due to the lack of a fragment of DNA that “falls” at the time of conception of a child – with a probability of approximately 1: 20,000 this happens in perfectly healthy parents. The missing region contains 25 to 28 protein-coding genes. The study of the least studied of them – WBSCR27 (Williams-Beuren syndrome chromosomal region 27), scientists from Moscow State University named after MV Lomonosov (Moscow). The authors compared the amino acid sequence of the corresponding protein with all proteins known to science and found that it has similar characteristics to representatives of the class of methyltransferases that transfer the methyl group (CH3-) to other molecules and that often play a regulatory role in cells .

To find out if the protein really belongs to methyltransferases, MSU researchers checked which molecules it can interact with and found that WBSCR27 forms very strong bonds with S-adenosyl-L-methionine. This molecule acts as a CH3 group donor for most known methyltransferases, and since the protein is able to bind to this molecule, it should most likely be able to transfer the methyl group. The scientists set up a series of experiments in which they tried to carry out the reaction of WBSCR27 with several potential targets, but it did not interact with any of them. To find out what the protein is most likely to react with, the researchers determined its spatial structure.

“To determine the structure of the protein, we needed to carry out long experiments in powerful nuclear magnetic resonance spectrometers. Our laboratory also has such a device, but its power is not sufficient for this type of experiments, so we needed to use spectrometers located in three more laboratories with which we have a cooperation agreement: Academia Sinica in Taiwan, Kazan Federal University and People’s Friendship University in Russia.This is how we determined the structure of the WBSCR27 protein in solution with a resolution down to individual atoms. says Sofya Maryasina, one of the study’s authors, a leading engineer at the Institute of Functional Genomics at Moscow State University. — Comparison of the resulting model with the structures of other proteins showed that the main structural core of the protein forms a fold characteristic of methyltransferases. However, our protein also has mobile sites that appear to be responsible for binding to potential targets. They have no analogues among known proteins. So at the moment it is impossible to say exactly what the WBSCR27 protein does in cells, but it is clear that it transfers a methyl group somewhere.“.

There are many examples where it is the incorrect functioning of methyltransferases that leads to the onset of serious diseases. For example, the replacement of a single DNA “letter” (the so-called point mutation) in the EMG1 methyltransferase gene causes Bowen-Conradi syndrome: growth failure and profound psychomotor retardation, leading to death in early childhood. A mutation in the gene for another methyltransferase (Cdkal1) leads to difficulties in the maturation of insulin, which causes diabetes. Incorrect DNA methylation is responsible for a number of autoimmune diseases (eg, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis), and also plays an important role in the development of cancer and the aging process.

Based on this information, scientists suggest that it is the WBSCR27 protein that may be responsible for severe pathologies in Williams syndrome. They hope that the structure they have defined will help answer this question and pave the way to treat the disease.

The study involved employees from the Faculty of Fundamental Medicine of Moscow State University, the Faculty of Chemistry of Moscow State University, the Institute of Functional Genomics of Moscow State University, the Sinica Academy (Taiwan), the KFU, the IBMMH, the RUDN University and Skoltech.

Prepared by Sofya Maryasina as part of the course on science journalism of the Student Union Committee of the Faculty of Biology, Moscow State University

Press Service of Moscow State University


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