Verification of alternative splicing variants based on domain integrity, truncation length and intrinsic protein disorder.

TitleVerification of alternative splicing variants based on domain integrity, truncation length and intrinsic protein disorder.
Publication TypeJournal Article
Year of Publication2011
AuthorsHegyi, H., L. Kalmar, T. Horvath, and P. Tompa
JournalNucleic Acids Res
Volume39
Issue4
Pagination1208-19
Date Published2011 Mar
ISSN1362-4962
KeywordsAlternative Splicing, Databases, Protein, Genetic Variation, Humans, Hydrophobic and Hydrophilic Interactions, Models, Molecular, Protein Isoforms, Protein Structure, Tertiary, Sequence Analysis, Protein
Abstract

According to current estimations ∼95% of multi-exonic human protein-coding genes undergo alternative splicing (AS). However, for 4000 human proteins in PDB, only 14 human proteins have structures of at least two alternative isoforms. Surveying these structural isoforms revealed that the maximum insertion accommodated by an isoform of a fully ordered protein domain was 5 amino acids, other instances of domain changes involved intrinsic structural disorder. After collecting 505 minor isoforms of human proteins with evidence for their existence we analyzed their length, protein disorder and exposed hydrophobic surface. We found that strict rules govern the selection of alternative splice variants aimed to preserve the integrity of globular domains: alternative splice sites (i) tend to avoid globular domains or (ii) affect them only marginally or (iii) tend to coincide with a location where the exposed hydrophobic surface is minimal or (iv) the protein is disordered. We also observed an inverse correlation between the domain fraction lost and the full length of the minor isoform containing the domain, possibly indicating a buffering effect for the isoform protein counteracting the domain truncation effect. These observations provide the basis for a prediction method (currently under development) to predict the viability of splice variants.

DOI10.1093/nar/gkq843
Alternate JournalNucleic Acids Res.
PubMed ID20972208
PubMed Central IDPMC3045584