Abstract
BackgroundProtein sequence insertions/deletions (indels) can be introduced during evolution or through alternative splicing (AS). Alternative splicing is an important biological phenomenon and is considered as the major means of expanding structural and functional diversity in eukaryotes. Knowledge of the structural changes due to indels is critical to our understanding of the evolution of protein structure and function. In addition, it can help us probe the evolution of alternative splicing and the diversity of functional isoforms. However, little is known about the effects of indels, in particular the ones involving core secondary structures, on the folding of protein structures. The long term goal of our study is to accurately predict the protein AS isoform structures. As a first step towards this goal, we performed a systematic analysis on the structural changes caused by short internal indels through mining highly homologous proteins in Protein Data Bank (PDB).ResultsWe compiled a non-redundant dataset of short internal indels (2-40 amino acids) from highly homologous protein pairs and analyzed the sequence and structural features of the indels. We found that about one third of indel residues are in disordered state and majority of the residues are exposed to solvent, suggesting that these indels are generally located on the surface of proteins. Though naturally occurring indels are fewer than engineered ones in the dataset, there are no statistically significant differences in terms of amino acid frequencies and secondary structure types between the "Natural" indels and "All" indels in the dataset. Structural comparisons show that all the protein pairs with short internal indels in the dataset preserve the structural folds and about 85% of protein pairs have global RMSDs (root mean square deviations) of 2Å or less, suggesting that protein structures tend to be conserved and can tolerate short insertions and deletions. A few pairs with high RMSDs are results of relative domain positions of the proteins, probably due to the intrinsically dynamic nature of the proteins.ConclusionsThe analysis demonstrated that protein structures have the "plasticity" to tolerate short indels. This study can provide valuable guides in modeling protein AS isoform structures and homologous proteins with indels through placing the indels at the right locations since the accuracy of sequence alignments dictate model qualities in homology modeling.
Highlights
Protein sequence insertions/deletions can be introduced during evolution or through alternative splicing (AS)
The major goal of this paper is to investigate the impact of short internal indels on protein structures, especially for indels within secondary structures
A non-redundant dataset of short internal indels from highly homologous protein pairs The protein chains were first clustered into 11,541 groups using BLASTClust as described in the Methods section
Summary
Protein sequence insertions/deletions (indels) can be introduced during evolution or through alternative splicing (AS). Several groups at CASP8 (the 8th Community Wide Experiment on the Critical Assessment of Techniques for Protein Structure Prediction) used the same protein 2G39 as the template to model target protein T0438, but only three of nine models placed the insertion sequence (12 amino acids) in the right place [8]. Another infamous/famous example in indel positioning is the modeling of the long AS isoform of Piccolo C2A domain that has a nine-residue insertion in a loop. Instead of folding as part of the loop, the nine-residue insert displaces a b-strand that is pushed into the calcium-binding region through local rearrangement, leading to a dramatic change in calcium binding affinity [9]
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