“Phosphate marker” turned out to be important for regulation of protein, mutation of which causes leukemia

Newswise — Scientists from the Federal Research Centre “Fundamentals of Biotechnology” of the Russian Academy of Sciences showed that nucleolar protein nucleophosmin ( NPM1), the defection of which can cause the development of leukemia and other types of cancer, deals with its regulatory protein only by phosphorylation of nucleophosmin (including “phosphate marker” in its composition). It attaches to NPM1 due to special enzyme and completely changes the intension of binding of this protein with its regulatory partner.  Receiving the spatial structure of 14-3-3 complex with key portion of nucleophosmin, containing “phosphate marker”, opens possibilities for further development of new drugs against some types of cancer. The results of this research, supported by grant of the Russian Science Foundation (RNF) and Ministry of Science and Higher Education of the Russian Federation are published in magazine Biochemical and Biophysical Research Communications. The research was conducted with the support of national project “Science and Universities”.

Proteins are biological polymers, fulfilling various functions in our organism. For example, nucleophosmin (NPM1) regulates the life circle of cells, participates in the synthesis of other proteins, and also influences the survival and development of human neurons. By this, mutations of nucleophosmin can lead to acute myeloid leukemia (kind of leukemia), and scientists regard it as an important tumor marker and potential target for creating drugs.

The work of NPM1, its folding and position in cell is controlled with the help of exactly coordinated mechanisms, one of which is the cooperation with special regulatory proteins from 14-3-3 family. In order to influence the work of NPM1, proteins 14-3-3 cooperate with it in the area, which can contain “phosphate marker”. More earlier researches showed that it is necessary for cooperation with 14-3-3, however, the structure of complex between these two proteins remains unknown.

Scientists from the Federal Research Centre “Fundamentals of Biotechnology” of the Russian Academy of Sciences jointly with colleagues from University of Oregon (USA) studied molecular complex that is formed by cooperating of NPM1 with protein 14-3-3.  The authors cloned the genes of these two human proteins into the cells of E-coli.  The bacteria worked out necessary molecules, and then authors selected the needed proteins and defined the structure of their complex. For this aim NPM1 was connected with protein 14-3-3 with the help of artificial flexible strap, that enables to draw together the parts of proteins that must cooperate.

Obtained with the help of crystallography structure of complex of protein 14-3-3 with functionally important fragment nucleophosmin supports the perspectivity and universality of the later developed by authors approach, based on creating hybrid complexes 14-3-3-partner, for studying of various complexes with participation of proteins 14-3-3.