Systematic analysis of short internal indels and their impact on protein folding.
Systematic analysis of short internal indels and their impact on protein folding.
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DOI：
10.1186/1472-6807-10-24
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发表时间：
2010-08-04
影响因子：
--
通讯作者：
Guo JT
中科院分区：
文献类型：
--
作者：
Kim R;Guo JT
蛋白质序列插入/缺失（indel）可以在进化过程中或通过选择性剪接（AS）引入。选择性剪接是一种重要的生物学现象，被认为是真核生物扩大结构和功能多样性的主要手段。由于插入缺失的结构变化的知识是至关重要的，我们的蛋白质结构和功能的进化的理解。此外，它可以帮助我们探索可变剪接的进化和功能异构体的多样性。然而，很少有人知道的影响indels，特别是那些涉及核心二级结构，蛋白质结构的折叠。本研究的长期目标是准确预测蛋白质AS异构体的结构。作为实现这一目标的第一步，我们通过挖掘蛋白质数据库（PDB）中高度同源的蛋白质，对短的内部indel引起的结构变化进行了系统的分析。我们从高度同源的蛋白质对中编译了一个非冗余的短内部indel（2-40个氨基酸）数据集，并分析了indel的序列和结构特征。我们发现大约三分之一的indel残基处于无序状态，并且大部分残基暴露于溶剂中，这表明这些indel通常位于蛋白质的表面。虽然数据集中天然存在的indel比工程化的少，但数据集中“天然”indel和“所有”indel之间的氨基酸频率和二级结构类型没有统计学显著差异。结构比较表明，数据集中所有具有短内部插入缺失的蛋白质对都保留了结构折叠，约85%的蛋白质对的全局均方根偏差（均方根偏差）为2 μ m或更小，表明蛋白质结构趋于保守，可以容忍短插入和缺失。具有高RMSD的少数对是蛋白质的相对结构域位置的结果，可能是由于蛋白质的内在动态性质。分析表明，蛋白质结构具有“可塑性”，以容忍短indel。该研究可以提供有价值的指导蛋白质AS异构体结构和同源蛋白质的建模与indel通过放置在正确的位置，因为序列比对的准确性决定了同源建模的模型质量。
Protein 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). We 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. The 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.
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