Biological Impact Of Mutually Exclusive Exon Switching

Alternative splicing can expand the diversity of proteomes. Homologous mutually exclusive exons (MXEs) originate from the same ancestral exon and result in polypeptides with similar structural properties but altered sequence. Why would some genes switch homologous exons and what are their biological impact? Here, we analyse the extent of sequence, structural and functional variability in MXEs and report the first large scale, structure-based analysis of the biological impact of MXE events from different genomes. MXE-specific residues tend to map to single domains, are highly enriched in surface exposed residues and cluster at or near protein functional sites. Thus, MXE events are likely to maintain the protein fold, but alter specificity and selectivity of protein function. This comprehensive resource of MXE events and their annotations is available at: . These findings highlight how small, but significant changes at critical positions on a protein surface are exploited in evolution to alter function.Author summaryA single gene can produce more than one protein through processes such as Alternative Splicing. Mutually exclusive splicing is one type of splicing by which cells produce isoforms that are often very similar in their three-dimensional shape. Different transcript isoforms are usually produced in different cell tissues and cell environments. The structural impacts of this splicing are still not well-studied. In this study, we compare proteins generated from mutually exclusive exon switching from 5 organisms. Most of these proteins do not have their three-dimensional shape solved by experimental methods. We therefore calculate the most probable three-dimensional structural models. We found small regions that are different between the proteins and occur near important residue sites that determine the functions of the proteins. We speculate mutually exclusive splicing may be involved in tuning the protein function. We have built a webserver to present information on these exon switching events: http://gene3d.biochem.ucl.ac.uk/mxemod/.