Human gene regulation mechanism discovered
Scientists from Germany, Spain and France say you must transcribe a protein-coding gene into ribonucleic acid (RNA) and in the 'splicing process' shortened to the correct template if you want to produce proteins. In their latest study, presented in the journal Nature, the researchers provide new insight into how the U2AF protein enables this process. The research was funded in part by three EU projects with a combined total of EUR 25.4 million under the Sixth Framework Programme (FP6). Led by the Helmholtz Zentrum München and the Technical University of Munich (TUM) in Germany, the researchers discovered how the U2AF protein enables the pre-messenger RNA (pre-mRNA), which serves as a template for protein synthesis in the body. The pre-mRNA must first be transcribed from the deoxyribonucleic acid (DNA). Various proteins, what experts call splicing factors, need to work together to ensure the success of splicing, which plays a crucial role in the central system of molecular biology. That is, genetic data moves in one direction: from DNA to RNA, and then on to proteins. There is a specific structure contained in the genes of the human genome. Areas with key exons alternate with areas researchers call introns, which hold irrelevant data that do not encode the corresponding protein. Some members of the team assessed U2AF; this is a splicing factor that consists of two structural modules and binds to the RNA near the intron-exon boundary. The pre-mRNA copy is spliced and the introns are removed. So the mRNA that is left consists only of exons, which encode the amino acid sequence of a given protein. 'The spatial structure of the U2AF protein alternates between a closed and an open conformation,' explains Professor Michael Sattler, head of the Institute for Structural Biology at the Helmholtz Zentrum München and professor of Biomolecular NMR [nuclear magnetic resonance] Spectroscopy at TUM. 'A matching RNA sequence in the intron causes the U2AF to assume an open conformation, which activates splicing and eventually leads to the removal of the intron.' According to the researchers, the RNA sequence of the intron determines how effectively this conformational change can be activated. A process of conformational selection helps bring on a shift of balance between the closed and open form of the U2AF protein. In effect, the RNA binds to a tiny fraction of the open conformation that exists, regardless of RNA presence or absence. They believe that similar mechanisms can contribute significantly to the regulation of a number of other signal pathways in the cell. 'Our results indicate that the tandem RRM domains of U2AF65 do not simply act as a binding scaffold but instead have an active role in quantitatively relating Py tract strength to splice site recognition and spliceosome assembly,' the authors write in the paper. 'Multi-domain conformational selection of the open states allows the tandem RRM domains to function as a molecular rheostat with regard to U2AF activity during early steps of splicing, involving a competition for RRM1 between binding RRM2 (autoinhibition in a closed conformation) and RNA (activation by an open conformation). This provides a selectivity filter against promiscuous RNA binding and spliceosome assembly, as the higher affinity Py tract ligands are better able to counteract the energetic penalty needed for both RRM domains to bind.' The study was funded by the following EU projects, all under the 'Life sciences, genomics and biotechnology for health' Thematic area of FP6: 3D-REPERTOIRE, FSG-V-RNA, and EURASNET. 3D-REPERTOIRE ('A multidisciplinary approach to determine the structures of protein complexes in a model organism') received EUR 13 million in funding. FSG-V-RNA ('Functional and structural genomics of viral RNA') was backed with EUR 2.4 million, while EURASNET ('European alternative splicing network of excellence') was funded to the tune of EUR 10 million.For more information, please visit: Nature: http://www.nature.com/(opens in new window) Helmholtz Zentrum München: http://www.helmholtz-muenchen.de/en/start/index.html(opens in new window)
Countries
Germany, Spain, France