PTMD: A Database of Human Disease-associated Post-translational Modifications

Abstract

Various posttranslational modifications (PTMs) participate in nearly all aspects of biological processes by regulating protein functions, and aberrant states of PTMs are frequently implicated in human diseases. Therefore, an integral resource of PTM-disease associations (PDAs) would be a great help for both academic research and clinical use. In this work, we reported PTMD, a well-curated database containing PTMs that are associated with human diseases. We manually collected 1950 known PDAs in 749 proteins for 23 types of PTMs and 275 types of diseases from the literature. Database analyses show that phosphorylation has the largest number of disease associations, whereas neurologic diseases have the largest number of PTM associations. We classified all known PDAs into six classes according to the PTM status in diseases and demonstrated that the upregulation and presence of PTM events account for a predominant proportion of disease-associated PTM events. By reconstructing a disease-gene network, we observed that breast cancers have the largest number of associated PTMs and AKT1 has the largest number of PTMs connected to diseases. Finally, the PTMD database was developed with detailed annotations and can be a useful resource for further analyzing the relations between PTMs and human diseases. PTMD is freely accessible at http://ptmd.biocuckoo.org.

Keywords: AKT1; Disease–gene network; PTM–disease association; Phosphorylation; Posttranslational modification.

Figure 1

The data in the PTMD database A. The percentage of different PTM super types that are associated with diseases. In PTMD, 23 types of PTMs were classified into 9 super-types. B. The percentage of different super-types of diseases in PTMD. In total, 275 types of diseases are classified into 26 super-types based on the tissue information. C. The number of disease associations within each type of disease-associated PTMs. D. The number of disease associations within each type of PDAs for each PTM super-type. Blocks with different colors represent different types of PDAs, while the block length represents the number of PDAs for each PTMs. E. The distribution of the six types of PDAs for each disease super-type. The dot size represents the number of PDAs for each disease. U and D indicate that the PTM level is upregulated and downregulated in diseases, respectively; P and A indicate that the presence and absence of a PTM event is associated with disease progression, respectively. C indicates that a mutation event (single amino acid or indel mutations) creates one or multiple PTM sites or increases the protein PTM level in diseases, whereas N indicates that a mutation event disrupts one or multiple PTM sites or reduces the protein PTM levels in diseases. PTM, posttranslational modification; PDA, PTM–disease association.

Figure 2

The browse options of PTMD We provided two options to browse the database: by PTMs (A) and by diseases (C). B. All phosphorylated substrates with different PTM types of phosphorylation (tyrosine, threonine, and serine phosphorylation) are shown in a tabular format. D. All specific types of breast diseases, such as breast cancer and mammary tumor, are shown. E. The detailed information of human p53 in PTMD database, including Protein Information, PTM–Disease Association, Disease Cross-ref Annotation, PTM Sites, and Protein–Protein Interaction.

Figure 3

The search and advance options A. The database can be directly searched with one or multiple keywords. B. Advanced query allows users to input up to three search terms. C. Batch query allows users to query multiple keywords in a line-by-line format. D. Blast search option interrogates a protein sequence for detecting identical or homologous sequences.

Figure 4

A disease–gene network A. The network was visualized with Cytoscape v3.6.0 . B. The top ten diseases with the largest number of associations with PTM substrates. C. The top ten genes with the largest number of associated diseases. D. The number of each PTM super-type in the top ten diseases. E. The numbers of each PTM super-type for the top ten genes. AD, Alzheimer’s disease; NSCLC, non-small-cell lung cancer.