New mechanisms for human developmental diseases caused by the separation of protein fluids are revealed

why do two diseases, Noonan syndrome and leopard skin syndrome, two diseases caused by different types of genetic mutations, have very similar clinical symptoms? A new study by Chinese scientists has solved the long-standing mystery of the scientific community.Researcher
Researcher, Shanghai Organic Institute's Intersectional Research Center for Biology and Chemistry Shanghai Organic Institute's Cross-Research Center for Biology and Chemistry was established in 2012 with the concept of cross-research on biology and chemistry, with the goal of revealing the pathogenesicity of major diseases in humans. "Responding to the 'card neck list', in the field of biomedicine, our "research list" focuses on major diseases (including neurodegenerative diseases, tumors, etc.) that will put a heavy burden on our national economic development, and discovers original drug targets and therapeutic drugs, which is in this direction. "
of the Shanghai Organic Institute's Cross-Research Center for Biology and Chemistry.
"liquid phase separation" of biological molecules is a breakthrough development direction in the field of life science in recent years. Studies have shown that protein phase separation is widespread in cells, driving a variety of important biological functions. "Liquid phase separation" not only plays an important role in the physiological process, but also is closely related to the pathological processes of many major diseases in human beings, including tumors, autoimmune diseases, and neurodegenerative diseases.
non-subject tyrosine phosphatase SHP2 play a key role in RAS/MAPK signaling. Mutations in the SHP2 protein are associated with a variety of human diseases, including 50 percent of People with Noonan Syndrome and 90 percent of people with Leopard Skin Syndrome who carry SHP2's embryo hybrid mutation. SHP2 phosphatase activity is regulated by changes in its own composition, when the protein is in a "off" state, phosphatase activity is inhibited, and when the protein is "on" state, phosphatase activity is activated. The SHP2 mutation in Noonan syndrome causes SHP2 to be "opened" and causes the activity of the SHP2 enzyme to be activated. Mutations in leopard skin syndrome are located in the SHP2 catalytic domain, which makes the function of SHP2 phosphatase inactive.
, patients with two developmental disorders, Noonan syndrome and leopard skin syndrome, have very similar clinical symptoms. Why does the SHP2 mutation with missing enzyme activity and the SHP2 mutation with increased enzyme activity lead to clinical esophageal-like diseases?
in order to find out, Zhu Jidong and Liu Cong jointly carried out the research. "Liu Cong's research team has long focused on protein phase separation and major human disease research, and my research team is dedicated to the study of pathogenic pathogenesies and drug development of important diseases with SHP2 at its core." Zhu Jidong told China Science Daily, "The results of our cooperation perfectly combine each other's research advantages." After
two years of joint research, the team found for the first time that the SHP2 mutations present in Noonan syndrome and leopard skin syndrome promote abnormal fluid phase separation of the SHP2 protein in vitro and in cells.
study showed that the mutation of the SHP2 protein phase separation is mediated by the electrostatial interaction of the electrostatial charge on the surface of the phosphatase catalytic domain, and that the ability to separate the SHP2 phase is regulated by changes in the protein's composition. More importantly, phase separation of SHP2 mutants is essential for the activation of the RAS-MAPK path, and the phase separation formed by SHP2 mutants can recruit wild-type SHP2 proteins, increase enzyme concentration in local areas, promote SHP2 phosphatase function, and thus activate the MAPK signaling path.
results reveal for the first time the ability of phosphatase proteins to phase separation, suggesting that phase separation may be an important way for cells to regulate phosphatase activity;
at the same time, the study found that the SHP2 variant inhibitor ET070 inhibited the phase separation ability of the SHP2 mutant protein by locking the SHP2 protein in the "off" configuration, providing a new strategy for small molecule drugs to regulate phosphatase function and related disease treatment. "The SHP2 variant inhibitor ET070 was developed by a biopharmaceutical company in collaboration with us, and the compound has excellent in vitro and in vivo activity. It is also an important development direction of our cross-center to accelerate the breakthrough and development of biomedicine in China by combining basic scientific research with industry. Zhu Jidong explains.
experts believe that the results for the first time found that the phase separation abnormal regulation of enzymes play an important role in human developmental diseases. It is proposed to target protein function by regulating protein phase by small molecules, to provide theoretical basis for the treatment of related diseases, and to help develop small molecule drugs to treat such diseases, so as to bring light to patients.
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