Human proteins with target sites of multiple post-translational modification types are more prone to be involved in
Qianli Huang1, Jinhui Chang, Man Kit Cheung
1School of Life Sciences, The Chinese University of Hong Kong , Shatin, Hong Kong SAR 852000, China.
Abstract:
Many proteins can be modified by multiple types of post-translational modifications (Mtp-proteins). Although some post-translational modifications (PTMs) have recently been found to be associated with life-threatening diseases like cancers and neurodegenerative disorders, the underlying mechanisms remain enigmatic to date. In this study, we examined the relationship of human Mtp-proteins and disease and systematically characterized features of these proteins. Our results indicated that Mtp-proteins are significantly more inclined to participate in disease than proteins carrying no known PTM sites. Mtp-proteins were found significantly enriched in protein complexes, having more protein partners and preferred to act as hubs/superhubs in protein-protein interaction (PPI) networks. They possess a distinct functional focus, such as chromatin assembly or disassembly, and reside in biased, multiple subcellular localizations. Moreover, most Mtp-proteins harbor more intrinsically disordered regions than the others. Mtp-proteins carrying PTM types biased toward locating in the ordered regions were mainly related to protein-DNA complex assembly. Examination of the energetic effects of PTMs on the stability of PPI revealed that only a small fraction of single PTM events influence the binding energy of >2 kcal/mol, whereas the binding energy can change dramatically by combinations of multiple PTM types. Our work not only expands the understanding of Mtp-proteins but also discloses the potential ability of Mtp-proteins to act as key elements in disease development.
Insights
Many proteins with multiple post-translational modifications (PTMs) are linked to diseases. These Mtp-proteins play crucial roles in cellular processes and disease development, often acting as network hubs.
Area of Science:
- Molecular Biology
- Systems Biology
- Biochemistry
Background:
- Proteins undergo post-translational modifications (PTMs) that regulate their function.
- Proteins with multiple PTM types (Mtp-proteins) are increasingly associated with diseases like cancer.
- Mechanisms linking Mtp-proteins to disease pathogenesis are not well understood.
Purpose of the Study:
- To investigate the association between human Mtp-proteins and disease.
- To systematically characterize the features of Mtp-proteins.
- To explore the role of Mtp-proteins in disease development.
Main Methods:
- Analysis of human Mtp-protein datasets.
- Characterization of protein features, including PTM sites, protein-protein interactions (PPIs), and subcellular localization.
- Examination of intrinsically disordered regions and PTM effects on PPI stability.
Main Results:
- Mtp-proteins are significantly more involved in disease than proteins without PTMs.
- Mtp-proteins are enriched in protein complexes, act as network hubs, and have specific functional roles (e.g., chromatin dynamics).
- Combinations of PTMs dramatically alter protein-protein interaction stability, more so than single PTM events.
Conclusions:
- Mtp-proteins are key players in disease development.
- Understanding Mtp-protein characteristics offers insights into disease mechanisms.
- PTM combinations significantly impact protein interactions and cellular functions relevant to disease.
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