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Published on: March 24, 2019
Loss of post-translational modification sites in disease
Shuyan Li1, Lilia M Iakoucheva, Sean D Mooney
1School of Informatics and Computing, Indiana University, Bloomington, IN 47408, USA.
Abstract:
Understanding and predicting molecular cause of disease is one of the major challenges for biology and medicine. One particular area of interest continues to be computational analyses of disease-associated amino acid substitutions. To this end, various studies have been performed to identify molecular functions disrupted by disease-causing mutations. Here, we investigate the influence of disease-associated mutations on post-translational modifications. In particular, we study the loss of modification target sites as a consequence of disease mutation. We find that about 5% of disease-associated mutations may affect known modification sites, either partially (4%) of fully (1%), compared to about 2% of putatively neutral polymorphisms. Most of the fifteen post-translational modification types analyzed were found to be disrupted at levels higher than expected by chance. Molecular functions and physiochemical properties at sites of disease mutation were also compared to those of neutral polymorphisms involved in the process of post-translational modification site disruption. Disease-associated mutations in the neighborhood of post-translationally modified sites were found to be enriched in mutations that change polarity, charge, and hydrophobicity of the wild-type amino acids. Overall, these results further suggest that disruption of modification sites is an important but not the major cause of human genetic disease.
Insights
Disease mutations can disrupt protein modification sites, impacting biological functions. Our study reveals that while 5% of disease mutations affect these sites, it
Area of Science:
- Genomics and Bioinformatics
- Molecular Biology
- Computational Biology
Background:
- Identifying the molecular basis of diseases is a significant challenge in biology and medicine.
- Computational analysis of disease-associated amino acid substitutions is crucial for understanding disease mechanisms.
- Previous research focused on molecular functions disrupted by disease-causing mutations.
Purpose of the Study:
- To investigate the impact of disease-associated mutations on post-translational modifications (PTMs).
- To specifically analyze the loss of PTM target sites due to disease mutations.
- To compare the effects of disease mutations with neutral polymorphisms on PTM sites.
Main Methods:
- Analysis of disease-associated amino acid substitutions and their effect on known PTM sites.
- Comparison of PTM site disruption by disease mutations versus neutral polymorphisms.
- Evaluation of changes in molecular functions and physicochemical properties at mutated PTM sites.
Main Results:
- Approximately 5% of disease-associated mutations affect known PTM sites (4% partially, 1% fully).
- This is significantly higher than the 2% observed for neutral polymorphisms.
- Most of the fifteen PTM types analyzed showed disruption levels higher than expected by chance.
- Disease mutations near PTM sites are enriched for changes in polarity, charge, and hydrophobicity.
Conclusions:
- Disruption of post-translational modification sites by mutations is an important factor in human genetic diseases.
- However, this mechanism is not the primary driver of most human genetic diseases.
- The study highlights the role of altered physicochemical properties in disease-associated mutations affecting PTMs.
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