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Alternate Phosphorylation/O-GlcNAc Modification on Human Insulin IRSs: A Road towards Impaired Insulin Signaling in Alzheimer and Diabetes.

Jahangir Z, Ahmad W, Shabbiri K - Adv Bioinformatics (2014)

Bottom Line: Like phosphorylation, O-glycosylation modification is important PTM and inhibits phosphorylation on same or neighboring Ser/Thr residues, often called Yin Yang sites.Both IRS-1 and IRS-2 have been shown to be O-glycosylated; however exact sites are not determined yet.Moreover, alternative phosphorylation and O-glycosylation on IRS-1 Ser-312, 984, 1037, and 1101 may act as possible therapeutic targets to minimize the risk of AD and T2DM.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, GC University Lahore, Lahore, Pakistan.

ABSTRACT
Impaired insulin signaling has been thought of as important step in both Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Posttranslational modifications (PTMs) regulate functions and interaction of insulin with insulin receptors substrates (IRSs) and activate insulin signaling downstream pathways via autophosphorylation on several tyrosine (TYR) residues on IRSs. Two important insulin receptor substrates 1 and 2 are widely expressed in human, and alternative phosphorylation on their serine (Ser) and threonine (Thr) residues has been known to block the Tyr phosphorylation of IRSs, thus inhibiting insulin signaling and promoting insulin resistance. Like phosphorylation, O-glycosylation modification is important PTM and inhibits phosphorylation on same or neighboring Ser/Thr residues, often called Yin Yang sites. Both IRS-1 and IRS-2 have been shown to be O-glycosylated; however exact sites are not determined yet. In this study, by using neuronal network based prediction methods, we found more than 50 Ser/Thr residues that have potential to be O-glycosylated and may act as possible sites as well. Moreover, alternative phosphorylation and O-glycosylation on IRS-1 Ser-312, 984, 1037, and 1101 may act as possible therapeutic targets to minimize the risk of AD and T2DM.

No MeSH data available.


Related in: MedlinePlus

Graphical representation of the potential Ser, Thr, and Tyr residues for phosphorylation sites in human IRS-1 and IRS-2. (a) Predicted potential sites for phosphorylation on Ser, Thr, and Tyr residues. The light gray horizontal line shows the threshold for modification potential. The blue, green, and red vertical lines indicate the potential phosphorylated Ser, Thr, and Tyr residues, respectively. This graph was generated by NetPhos 2.0 web based program. (b) Predicted potential sites for phosphorylation on Ser, Thr, and Tyr residues. The light gray horizontal line shows the threshold for modification potential. The blue, green, and red vertical lines indicate the potential phosphorylated Ser, Thr, and Tyr residues, respectively. This graph was generated by NetPhos 2.0 web based program.
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fig5: Graphical representation of the potential Ser, Thr, and Tyr residues for phosphorylation sites in human IRS-1 and IRS-2. (a) Predicted potential sites for phosphorylation on Ser, Thr, and Tyr residues. The light gray horizontal line shows the threshold for modification potential. The blue, green, and red vertical lines indicate the potential phosphorylated Ser, Thr, and Tyr residues, respectively. This graph was generated by NetPhos 2.0 web based program. (b) Predicted potential sites for phosphorylation on Ser, Thr, and Tyr residues. The light gray horizontal line shows the threshold for modification potential. The blue, green, and red vertical lines indicate the potential phosphorylated Ser, Thr, and Tyr residues, respectively. This graph was generated by NetPhos 2.0 web based program.

Mentions: To predict phosphorylated residues in human IRS-1, NetPhos was used. Figure 5(a) is a graphical representation of phosphorylation potential of the Ser, Thr, and Tyr residues in IRS-1. NetPhos predicted phosphorylation on 113 Ser, 13 Thr, and 20 Tyr residues including all experimentally verified phosphorylation sites except Ser-323, 374, 794 and Thr-530 and 1111 as shown in Table S1 available online at http://dx.doi.org/10.1155/2014/324753.


Alternate Phosphorylation/O-GlcNAc Modification on Human Insulin IRSs: A Road towards Impaired Insulin Signaling in Alzheimer and Diabetes.

Jahangir Z, Ahmad W, Shabbiri K - Adv Bioinformatics (2014)

Graphical representation of the potential Ser, Thr, and Tyr residues for phosphorylation sites in human IRS-1 and IRS-2. (a) Predicted potential sites for phosphorylation on Ser, Thr, and Tyr residues. The light gray horizontal line shows the threshold for modification potential. The blue, green, and red vertical lines indicate the potential phosphorylated Ser, Thr, and Tyr residues, respectively. This graph was generated by NetPhos 2.0 web based program. (b) Predicted potential sites for phosphorylation on Ser, Thr, and Tyr residues. The light gray horizontal line shows the threshold for modification potential. The blue, green, and red vertical lines indicate the potential phosphorylated Ser, Thr, and Tyr residues, respectively. This graph was generated by NetPhos 2.0 web based program.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4281456&req=5

fig5: Graphical representation of the potential Ser, Thr, and Tyr residues for phosphorylation sites in human IRS-1 and IRS-2. (a) Predicted potential sites for phosphorylation on Ser, Thr, and Tyr residues. The light gray horizontal line shows the threshold for modification potential. The blue, green, and red vertical lines indicate the potential phosphorylated Ser, Thr, and Tyr residues, respectively. This graph was generated by NetPhos 2.0 web based program. (b) Predicted potential sites for phosphorylation on Ser, Thr, and Tyr residues. The light gray horizontal line shows the threshold for modification potential. The blue, green, and red vertical lines indicate the potential phosphorylated Ser, Thr, and Tyr residues, respectively. This graph was generated by NetPhos 2.0 web based program.
Mentions: To predict phosphorylated residues in human IRS-1, NetPhos was used. Figure 5(a) is a graphical representation of phosphorylation potential of the Ser, Thr, and Tyr residues in IRS-1. NetPhos predicted phosphorylation on 113 Ser, 13 Thr, and 20 Tyr residues including all experimentally verified phosphorylation sites except Ser-323, 374, 794 and Thr-530 and 1111 as shown in Table S1 available online at http://dx.doi.org/10.1155/2014/324753.

Bottom Line: Like phosphorylation, O-glycosylation modification is important PTM and inhibits phosphorylation on same or neighboring Ser/Thr residues, often called Yin Yang sites.Both IRS-1 and IRS-2 have been shown to be O-glycosylated; however exact sites are not determined yet.Moreover, alternative phosphorylation and O-glycosylation on IRS-1 Ser-312, 984, 1037, and 1101 may act as possible therapeutic targets to minimize the risk of AD and T2DM.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, GC University Lahore, Lahore, Pakistan.

ABSTRACT
Impaired insulin signaling has been thought of as important step in both Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Posttranslational modifications (PTMs) regulate functions and interaction of insulin with insulin receptors substrates (IRSs) and activate insulin signaling downstream pathways via autophosphorylation on several tyrosine (TYR) residues on IRSs. Two important insulin receptor substrates 1 and 2 are widely expressed in human, and alternative phosphorylation on their serine (Ser) and threonine (Thr) residues has been known to block the Tyr phosphorylation of IRSs, thus inhibiting insulin signaling and promoting insulin resistance. Like phosphorylation, O-glycosylation modification is important PTM and inhibits phosphorylation on same or neighboring Ser/Thr residues, often called Yin Yang sites. Both IRS-1 and IRS-2 have been shown to be O-glycosylated; however exact sites are not determined yet. In this study, by using neuronal network based prediction methods, we found more than 50 Ser/Thr residues that have potential to be O-glycosylated and may act as possible sites as well. Moreover, alternative phosphorylation and O-glycosylation on IRS-1 Ser-312, 984, 1037, and 1101 may act as possible therapeutic targets to minimize the risk of AD and T2DM.

No MeSH data available.


Related in: MedlinePlus