The number of genes in humans, mice and fruit flies is almost identical, around 20.000, and thus cannot explain the phenotypic differences between these organisms. Thus, for the evolution of life not only the number of genes but also the regulation of these genes plays a critical role. Upon transcription of the DNA, mRNA is produced as an initial step, which subsequently functions as template for the synthesis of proteins. Protein synthesis is regulated by the binding of regulatory proteins to the mRNA. How these proteins specifically recognize the RNA has been poorly understood to date.
An international team, led by Helmholtz Zentrum München (HMGU) and Technische Universität München (TUM), has now determined the three-dimensional structure of such a regulatory protein-RNA-complex. Crystallography and NMR spectroscopy analysis performed by the Munich team was complemented with small angle scattering data performed at the Institut Laue Langevin in Grenoble. The scientists studied the specific complex formed between the regulatory proteins Sxl (Sex-lethal) and Unr (Upstream-of-N-Ras) with mRNA in the fruit fly model. This protein complex is essential to ensure that the expression of genes located on the two female (XX) X-chromosomes equals that of genes located on the single male (XY) X-chromosome. This guarantees that comparable protein concentrations are achieved in both sexes, which is essential for viability of fruit flies.
A paradigm for gene regulation
The three-dimensional structure now reveals how multiple proteins collaborate for highly specific recognition of the mRNA. “Our results represent a paradigm for the regulation of various essential cellular processes at the level of mRNA”, explains Sattler, director of the Institute of Structural Biology at HMGU. The specific recognition of mRNA is achieved by cooperation of several RNA-binding proteins, even though these proteins individually exhibit poor binding affinity and are involved in distinct 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.
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 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 Biologie Structurale (Grenoble, France).
Dr. Grzegorz Popowicz, Miriam Sonntag, Dr. Janosch Hennig, Prof. Michael Sattler (left to right), Source: Helmholtz Zentrum München
* NMR= Nuclear Magnetic Resonance
Hennig, J. et al. (2014). Structural basis for the assembly of the SXL-UNR translation regulatory complex, Nature, doi: 10.1038/nature13693
Helmholtz Zentrum München, as German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the diagnosis, treatment and prevention of major widespread diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The head office of the Center is located in Neuherberg in the north of Munich. Helmholtz Zentrum München has a staff of about 2,200 people and is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 34,000 staff members.
The Institute for Structural Biology (STB) investigates the spatial structures of biological macromolecules, their molecular interactions and dynamics using integrated structural biology by combining X-ray crystallography, NMR-spectroscopy and other methods. Researchers at STB also develop NMR spectroscopy methods for these studies. The goal is to unravel the structural and molecular mechanisms underlying biological function and their impairment in disease. The structural information is used for the rational design and development of small molecular inhibitors in combination with chemical biology approaches.
Technische Universität München (TUM) is one of Europe’s leading research universities, with around 500 professors, 10,000 academic and non-academic staff, and 36,000 students. Its focus areas are the engineering sciences, natural sciences, life sciences and medicine, reinforced by schools of management and education. TUM acts as an entrepreneurial university that promotes talents and creates value for society. In that it profits from having strong partners in science and industry. It is represented worldwide with a campus in Singapore as well as offices in Beijing, Brussels, Cairo, Mumbai, and São Paulo. Nobel Prize winners and inventors such as Rudolf Diesel and Carl von Linde have done research at TUM. In 2006 and 2012 it won recognition as a German “Excellence University.” In international rankings, it regularly places among the best universities in Germany.
Prof. Michael Sattler, Helmholtz Zentrum München – German Research Center for Environmental Health (GmbH), Institute for Structural Biology, Ingolstädter Landstr. 1, 85764 Neuherberg – Phone: +40-(0)89-3187-3800 – Email