How can one gene code for several proteins? New elements published in Nature

Over 100 000 genes in wheat and only 30 000 in humans… Since 2003, genome sequencing has produced perplexing results, which are compelling biologists to focus on splicing, a process which can explain why advanced organisms such as humans contain a limited number of genes. IECB group leader Cameron Mackereth, together with colleagues from Spain and Germany, has now discovered how the human U2AF protein enables this process. The results were published online on July 13^th in Nature.

The information carried by our genome in the form of DNA goes through a number processes before it can translate into proteins, which we need to perform most of our cellular functions. First, a pre-messenger RNA is copied from the DNA. The pre-mRNA is composed of non-coding segments (introns) and of segments which are coding for proteins (exons). Some of these segments are then removed during the splicing process to form the final mRNA, which serves as a corrected blueprint for protein synthesis in the body. Depending on the segments which are removed, several mRNAs can result from the same pre-mRNA sequence. This has led scientists to estimate that 70% of our genes code for at least 4 proteins each.     

Splicing requires the cooperation of different proteins, or splicing factors. One such splicing factor, U2AF, was examined by Dr Cameron Mackereth from IECB (Inserm U869/Université Bordeaux Segalen), together with colleagues from the Helmholtz Zentrum München and the Technical University of Munich (TUM), the European Molecular Biology Laboratory (EMBL) in Heidelberg and the Centre for Genomic Regulation in Barcelona.

They found that the spatial structure of the U2AF protein alternates between a closed conformation that is inactive, and an open active form that triggers intron removal. Intron sequences vary in their ability to selectively bind and stabilize the active conformation, thus resulting in diverse patterns of intron elimination, and an increase in the number of different proteins made by a single gene. Disruption of this key process in splicing may be involved in many diseases, including cancer. The scientists also presume that a similar shape-shifting mechanism plays an important role in the regulation of many other signal pathways in the cell.

Cameron D. Mackereth, Tobias Madl, Sophie Bonnal, Bernd Simon, Katia Zanier, Alexander Gasch, Vladimir Rybin, Juan Valcárcel & Michael Sattler (2011) Multi-domain conformational selection underlies pre-mRNA splicing regulation by U2AF, Nature, doi:10.1038/nature10171