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New mechanism in gene regulation revealed

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New mechanism in gene regulation revealed

a–f, Overview (a) of the ternary complex of Sxl dRBD3 (green), Unr CSD1 (blue) and msl2 RNA (magenta) and zoomed views (b–f) of specific interactions as indicated. g, Schematic overview of important structural features and binding interfaces in the ternary complex. Sxl β1, β1-strand of Sxl-RRM1.
September 2014

Scientists working at the Institut Laue-Langevin have unraveled a molecular mechanism of messenger RNA (mRNA) recognition, which is essential for understanding gene regulation in male and female organisms. The study published in Nature helps explain how biological messenger molecules transfer their genetic instructions (or 'script') for the building of proteins – proteins that determine all the biological functions which we see in living organisms and which separate us humans from mice, fruit flies and every other living organism.

Another difference in genes is those that define gender. It’s well-known that females have two X-chromosomes and males have one X-chromosome and one Y-chromosome. The number of proteins from the X-chromosome is doubled in females and it is essential that the expression of genes in females is regulated to ensure comparable protein concentrations in both sexes; this is known as dosage compensation. Whilst it has been known for some time that this dosage compensation takes place within genes, it has not been clear exactly where and how the mechanism occurs.

In this new study, an international team of scientists has determined the three-dimensional structure of these regulatory protein-RNA-complexes by studying the specific complex formed between the regulatory proteins Sxl (Sex-lethal) and Unr (Upstream-of-N-Ras) with mRNA in the Drosophila melanogaster fruit fly model.

Scientists from the Technische Universität München (TUM) visited the Institut Laue-Langevin in Grenoble to understand the molecular structures of the proteins involved. Using small angle neutron scattering (SANS), which allows each substance to be looked at individually, the research team, guided by ILL's Dr Frank Gabel, were able to locate where the two proteins sit in relation to the RNA. These studies complemented the second phase of the research, where three-dimensional crystallography was used to highlight the differences between the proteins and RNA. Together, these investigations revealed how multiple proteins collaborate for highly specific recognition of the mRNA.

Lead researcher Frank Gabel at the ILL (who is presently detached part-time from the Institut de Biologie Structurale, UJF/CNRS/CEA) stated: “This study has allowed us to look at the exact location of mRNA and proteins within the complex they form and how they interact with each other. This SANS scattering analysis was vital to the results of the study and helped the NMR (nuclear magnetic resonance) refinement process at Prof. Sattler’s lab at TUM. Using small-angle x-ray (SAXS) methods alone would not have revealed the exact location of the proteins and RNA, only a general envelope of what was happening. Crystallography, on the other hand, often tells a different story in and out of solution.”

The team’s results indicated that the specific recognition of mRNA is achieved by several RNA-binding proteins working together, even though they usually exhibit poor binding affinity and are involved in other processes in the cell. By combining multiple proteins, the number and variety of biological processes that can be regulated by a relatively small number of regulatory RNA binding proteins is greatly expanded. The authors expect that this principle represents an essential and widespread mechanism of gene regulation in higher organisms, where mutation or misregulation of homologous proteins has been implicated in disease.

Re.:  Nature, (2014), doi:10.1038/nature13693

The research was conducted by a group of scientists around Dr. Janosch Hennig, Dr. Grzegorz Popowicz and Professor Dr. Michael Sattler from Helmholtz Zentrum München (HMGU) and Technische Universität München (TUM) together with the group of Dr. Fátima Gebauer at the Centre for Genomic Regulation (Barcelona, Spain). X-ray crystallography and Nuclear Magnetic Resonance (NMR) spectroscopy experiments were performed at the Institute of Structural Biology of HMGU and the Bavarian NMR Centre (TUM und HMGU), small angle scattering was done by Dr. Frank Gabel at the Institut Laue-Langevin and the Institut de Biologie Structurale (UJF/CNRS/CEA) (Grenoble, France).