News from CRG
The Fas protein can either inhibit or promote the controlled cell death (apoptosis), depending on the isoform in which it occurs. Researchers from the Helmholtz Zentrum München, the Technical University of Munich, and the CRG, in collaboration with the Institute of Molecular Genetics of Montpeller, have elucidated how this decision is guided. These results provide new insights into the molecular mechanisms of tumor diseases and have now been published in 'eLife'.
An interesting example of alternative splicing is the mRNA of the Fas gene. Depending on which intermediate steps take place, the finished protein can either prevent or promote controlled cell death (apoptosis). "The right balance between these opposing results is dependent on the cell type and can also lead to uncontrolled cell growth and cancer when alternative splicing is dysregulated," explains Professor Michael Sattler, from the Helmholtz Zentrum München. In collaboration with Professor Juan Valcárcel Juárez of the Centre de Regulació Genòmica (CRG) in Barcelona, he and his team have now gained insight into which intermediate steps are taken and how these lead to different isoforms of the Fas protein.
"The focus of our interest was the protein RBM5, which often exhibits mutations in lung tumors," says Dr. André Mourão of the STB. "RBM5 helps to bring the spliceosome to the mRNA by binding to a spliceosomal protein", explains coauthor Dr. Sophie Bonnal of the CRG. In this central position, RBM5 decides which isoform of Fas is expressed and thus controls the balance between the two different isoforms. "By employing nuclear magnetic resonance (NMR) spectroscopy , we were able to elucidate the spatial structure of RBM5-OCRE in complex with SmN (a protein present in the spliceosome) and to understand exactly how these interaction occurs," states Sattler, who directed the study.
Mourão, A. & Bonnal, S. & Soni, K. & Warner, L. et al. (2016): Structural basis for the recognition of spliceosomal SmN/B/B’ proteins by the RBM5 OCRE domain in splicing regulation. eLife, doi: 10.7554/eLife.14707