Systematic Analysis of the Genetic Variability That Impacts SUMO Conjugation and Their Involvement in Human Diseases

Abstract

Protein function has been observed to rely on select essential sites instead of requiring all sites to be indispensable. Small ubiquitin-related modifier (SUMO) conjugation or sumoylation, which is a highly dynamic reversible process and its outcomes are extremely diverse, ranging from changes in localization to altered activity and, in some cases, stability of the modified, has shown to be especially valuable in cellular biology. Motivated by the significance of SUMO conjugation in biological processes, we report here on the first exploratory assessment whether sumoylation related genetic variability impacts protein functions as well as the occurrence of diseases related to SUMO. Here, we defined the SUMOAMVR as sumoylation related amino acid variations that affect sumoylation sites or enzymes involved in the process of connectivity, and categorized four types of potential SUMOAMVRs. We detected that 17.13% of amino acid variations are potential SUMOAMVRs and 4.83% of disease mutations could lead to SUMOAMVR with our system. More interestingly, the statistical analysis demonstrates that the amino acid variations that directly create new potential lysine sumoylation sites are more likely to cause diseases. It can be anticipated that our method can provide more instructive guidance to identify the mechanisms of genetic diseases.

Figure 1. The receiver operating characteristic (ROC) curves of SumoPred prediction on 10 training sets.

Figure 2. Schematic illustration of four of SUMOAMVRs, which include the change of an amino acid by lysine residue to create a potential new (Type I (+)) or remove an original lysine sumoylation site (Type I (−)); variations adjacent to sumoylation sites to create (Type II (+)) or remove (Type II (−)) sumoylation sites; and variations which may change the types of E3 ligase that recognize sumoylation sites, without changing the sumoylation site itself (Type III); variations adjacent to sumoylation sites and further transform the type of PTMs that it should have happened (Type IV).

Yellow amino acid residues are mutation residues, sumo represents the small ubiquitin-related modifier, and a lysine (K) linked with a sumo represents that this K can be sumoylated by E3 ligase. E3^a represents one type of lysine E3 ligase and E3^b is another type of lysine E3 ligase.

Figure 3. A two-sample logo of the compositional biases around the sumoylation sites compared to the non-sumoylation sites.

This logo was prepared using the web server http://www.twosamplelogo.org/ and only residues significantly enriched and depleted surrounding sumoylation sites (t-test, P-value <0.05) are shown.

Figure 4. The data statistics of pathway terms for disease-related sumoylation substrates on the background of normal sumoylation substrates.

The blue pillar represent the number of substrates of different pathway terms and the red pillar represent the percentage of the number of substrates of different pathway terms in all substrates. Statistical significance (P-value) gradually increased from top to bottom.