Structural implication of splicing stochastics.

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TitleStructural implication of splicing stochastics.
Publication TypeJournal Article
Year of Publication2009
AuthorsMelamud, E, Moult, J
JournalNucleic Acids Res
Volume37
Issue14
Pagination4862-72
Date Published2009 Aug
ISSN1362-4962
KeywordsAlternative Splicing, Amino Acid Sequence, Disease, Humans, Molecular Sequence Data, Protein Conformation, Protein Isoforms, Protein Stability, Sequence Alignment, Sequence Analysis, Protein, Stochastic Processes
Abstract

Even though nearly every human gene has at least one alternative splice form, very little is so far known about the structure and function of resulting protein products. It is becoming increasingly clear that a significant fraction of all isoforms are products of noisy selection of splice sites and thus contribute little to actual functional diversity, and may potentially be deleterious. In this study, we examine the impact of alternative splicing on protein sequence and structure in three datasets: alternative splicing events conserved across multiple species, alternative splicing events in genes that are strongly linked to disease and all observed alternative splicing events. We find that the vast majority of all alternative isoforms result in unstable protein conformations. In contrast to that, the small subset of isoforms conserved across species tends to maintain protein structural integrity to a greater extent. Alternative splicing in disease-associated genes produces unstable structures just as frequently as all other genes, indicating that selection to reduce the effects of alternative splicing on this set is not especially pronounced. Overall, the properties of alternative spliced proteins are consistent with the outcome of noisy selection of splice sites by splicing machinery.

DOI10.1093/nar/gkp444
Alternate JournalNucleic Acids Res.
PubMed ID19528068
PubMed Central IDPMC2724273
Grant ListP01 GM57890 / GM / NIGMS NIH HHS / United States