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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

Homology models of human IRS-1 and IRS-2 retrieved through I-TASSER. Five models were predicted as possible 3D structures for both IRS-1 and IRS-2 proteins. The best model for each protein was selected on the basis of Ramachandran plots and their geometrical configuration. (a) Human IRS-1 full-length predicted 3D structures by I-TASSER with Ramachandran plots and geometry. (b) Human IRS-2 predicted 3D structures by I-TASSER with Ramachandran plots and geometry.
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fig3: Homology models of human IRS-1 and IRS-2 retrieved through I-TASSER. Five models were predicted as possible 3D structures for both IRS-1 and IRS-2 proteins. The best model for each protein was selected on the basis of Ramachandran plots and their geometrical configuration. (a) Human IRS-1 full-length predicted 3D structures by I-TASSER with Ramachandran plots and geometry. (b) Human IRS-2 predicted 3D structures by I-TASSER with Ramachandran plots and geometry.

Mentions: On the basis of Ramachandran plot analysis we proposed predicted model #2 (Figure 3(a)) as possible 3D structure for IRS-1 protein. In this structure 94.7% residues were in Ramachandran allowed region with only 5.32% outliers. No residues with bad bonds were found while only 1.06% residues with bad angles were predicted. However, the cβ deviations for these predicted models were not predicted by server.


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)

Homology models of human IRS-1 and IRS-2 retrieved through I-TASSER. Five models were predicted as possible 3D structures for both IRS-1 and IRS-2 proteins. The best model for each protein was selected on the basis of Ramachandran plots and their geometrical configuration. (a) Human IRS-1 full-length predicted 3D structures by I-TASSER with Ramachandran plots and geometry. (b) Human IRS-2 predicted 3D structures by I-TASSER with Ramachandran plots and geometry.
© Copyright Policy
Related In: Results  -  Collection

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

fig3: Homology models of human IRS-1 and IRS-2 retrieved through I-TASSER. Five models were predicted as possible 3D structures for both IRS-1 and IRS-2 proteins. The best model for each protein was selected on the basis of Ramachandran plots and their geometrical configuration. (a) Human IRS-1 full-length predicted 3D structures by I-TASSER with Ramachandran plots and geometry. (b) Human IRS-2 predicted 3D structures by I-TASSER with Ramachandran plots and geometry.
Mentions: On the basis of Ramachandran plot analysis we proposed predicted model #2 (Figure 3(a)) as possible 3D structure for IRS-1 protein. In this structure 94.7% residues were in Ramachandran allowed region with only 5.32% outliers. No residues with bad bonds were found while only 1.06% residues with bad angles were predicted. However, the cβ deviations for these predicted models were not predicted by server.

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