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

Xu HD, Shi SP, Chen X, Qiu JD - Sci Rep (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Nanchang University, Nanchang 330031, P.R.China.

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.

No MeSH data available.


Related in: MedlinePlus

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. E3a represents one type of lysine E3 ligase and E3b is another type of lysine E3 ligase.
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f2: 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. E3a represents one type of lysine E3 ligase and E3b is another type of lysine E3 ligase.

Mentions: The information of human genetic variations was extracted from the SwissVariant database (2014_02). We collected total 12512 human variant proteins containing 68779 amino acid variations, of which including 24399 diseases’ variants, 37878 polymorphic and 6502 unclassified variants. These mutations are considered more likely to be involved in functional and causal effect in diseases, although biochemical confirmations of such causal effects were only available for some of the variants. On the basis of these data, we further exploited the SwissVariant, UniProtKB/Swiss-Prot, PhosphoSite-Plus, HPRD and a number of other databases about their underlying effects as well as the related references about these variations and the corresponding sumoylation information. With the SumoPred, the SUMOAMVR could be identified when the predicted results of sumoylation sites were altered between the original and variant sequences. In other words, if the status of sumoylation site of specific protein substrate is altered due to change of the residue types of the target sites or one or some key flanking amino acids in this fragment in the before and after mutagenesis, then we define these mutations are SUMOAMVR related. All SUMOAMVRs were classified into four types according to the consequences of their influence on the sumoylation sites which were defined as follows (Fig. 2):(i)Type I, an amino acid variation occurs at a sumoylation position that directly adds (Type I (+)) or removes (Type I (−)) the sumoylation site;(ii)Type II, the amino acid variations not occur at sumoylation positions but on the adjacent positions of sumoyaltion sites that add (Type II (+)) or remove (Type II(−)) the sumoylation sites; (iii) Type III SUMOAMVR are caused by changes in the types of E3 ligase involved, rather than in the sumoylation sites itself, regardless of the positions of the variations, that is to say, before the amino acid variation adjacent to sumoylation site occurs, the first kind of E3 ligase(expressed as E3a in Fig. 2) catalyzes lysine (K) and sumoylaiton happens, after the amino acid variation, the lysine sumoylation still happens, but the E3 ligase is changed to another type (expressed as E3b in Fig. 2);(iv) Type IV, the amino acid variations that occur on the adjacent positions of sumoyaltion sites may change the circumstance around the central lysine (K) and further transform the type of PTMs that it should have happened. For example, a lysine which should have be sumoylated might convert into acetylated or ubiquitylated because of the change of amino acids around the center lysine site. Due to the intricate mechanisms of various types PTMs and the unpredictability of transformation between different PTMs, we mainly investigate the first three types of SUMOAMVR and the thorough and comprehensive analysis of Type IV SUMOAMVR will be done in the subsequent work. (More detailed information about the classification method and specific examples could be viewed at: http://bioinfo.ncu.edu.cn/SUMOAMVR_Help.aspx.)


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

Xu HD, Shi SP, Chen X, Qiu JD - Sci Rep (2015)

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. E3a represents one type of lysine E3 ligase and E3b is another type of lysine E3 ligase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495600&req=5

f2: 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. E3a represents one type of lysine E3 ligase and E3b is another type of lysine E3 ligase.
Mentions: The information of human genetic variations was extracted from the SwissVariant database (2014_02). We collected total 12512 human variant proteins containing 68779 amino acid variations, of which including 24399 diseases’ variants, 37878 polymorphic and 6502 unclassified variants. These mutations are considered more likely to be involved in functional and causal effect in diseases, although biochemical confirmations of such causal effects were only available for some of the variants. On the basis of these data, we further exploited the SwissVariant, UniProtKB/Swiss-Prot, PhosphoSite-Plus, HPRD and a number of other databases about their underlying effects as well as the related references about these variations and the corresponding sumoylation information. With the SumoPred, the SUMOAMVR could be identified when the predicted results of sumoylation sites were altered between the original and variant sequences. In other words, if the status of sumoylation site of specific protein substrate is altered due to change of the residue types of the target sites or one or some key flanking amino acids in this fragment in the before and after mutagenesis, then we define these mutations are SUMOAMVR related. All SUMOAMVRs were classified into four types according to the consequences of their influence on the sumoylation sites which were defined as follows (Fig. 2):(i)Type I, an amino acid variation occurs at a sumoylation position that directly adds (Type I (+)) or removes (Type I (−)) the sumoylation site;(ii)Type II, the amino acid variations not occur at sumoylation positions but on the adjacent positions of sumoyaltion sites that add (Type II (+)) or remove (Type II(−)) the sumoylation sites; (iii) Type III SUMOAMVR are caused by changes in the types of E3 ligase involved, rather than in the sumoylation sites itself, regardless of the positions of the variations, that is to say, before the amino acid variation adjacent to sumoylation site occurs, the first kind of E3 ligase(expressed as E3a in Fig. 2) catalyzes lysine (K) and sumoylaiton happens, after the amino acid variation, the lysine sumoylation still happens, but the E3 ligase is changed to another type (expressed as E3b in Fig. 2);(iv) Type IV, the amino acid variations that occur on the adjacent positions of sumoyaltion sites may change the circumstance around the central lysine (K) and further transform the type of PTMs that it should have happened. For example, a lysine which should have be sumoylated might convert into acetylated or ubiquitylated because of the change of amino acids around the center lysine site. Due to the intricate mechanisms of various types PTMs and the unpredictability of transformation between different PTMs, we mainly investigate the first three types of SUMOAMVR and the thorough and comprehensive analysis of Type IV SUMOAMVR will be done in the subsequent work. (More detailed information about the classification method and specific examples could be viewed at: http://bioinfo.ncu.edu.cn/SUMOAMVR_Help.aspx.)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Nanchang University, Nanchang 330031, P.R.China.

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.

No MeSH data available.


Related in: MedlinePlus