Transcripts evolutionary conservation and structural dynamics give insights into the role of alternative splicing for the JNK family [article]

Adel Ait-hamlat, Lelia Polit, Hugues Richard, Elodie Laine
2017 bioRxiv   pre-print
Alternative splicing (AS), by producing several transcript isoforms from the same gene, has the potential to greatly expand the proteome in eukaryotes. Its deregulation has been associated to the development of various diseases, including cancer. Although the AS mechanisms are well described at the genomic level, little is known about the contribution of AS to protein evolution and the impact of AS at the level of the protein structure. Here, we address both issues by reconstructing the
more » ... nary history of the c-Jun N-terminal kinase (JNK) family, and by describing the tertiary structures and dynamical behavior of several JNK isoforms. JNKs bear a great interest for medicinal research as they are involved in crucial signaling pathways. We reconstruct the phylogenetic forest relating 60 JNK transcripts observed in 7 species. We use it to estimate the evolutionary conservation of transcripts and to identify ASEs likely to be functionally important. We show that ASEs of ancient origin and having significant functional outcome may induce very subtle changes on the protein's structural dynamics. We also propose that phylogenetic reconstruction, combined with structural modeling, can help identify new potential therapeutic targets. Finally, we show that transcripts likely non-functional (i.e. not conserved) display peculiar sequence and structural properties. Our approach is implemented in PhyloSofS (Phylogenies of Splicing Isoforms Structures), a fully automated computational tool that infers plausible evolutionary scenarios explaining a set of transcripts observed in several species and models the three-dimensional structures of the protein isoforms. PhyloSofS has broad applicability and can be used, for example, to study transcripts diversity between different individuals (e.g. patients affected by a particular disease). It is freely available at www.lcqb.upmc.fr/PhyloSofS.
doi:10.1101/119891 fatcat:cnyk3rk53ve6jggdzwoqh745pq