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Template:STRUCTURE 3pe4
O-GlcNAc transferase
O-linked beta-N-acetylglucosamine transferase (O-GlcNAc transferase) is an essential mammalian enzyme that acts as a nutrient sensor, coupling metabolic status to the regulation of a wide variety of cellular signaling pathways.[1] OGT catalyses the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine (UDP-GlcNAc) to serines and threonines of cytoplasmic, nuclear and mitochondrial proteins, including numerous transcription factors, tumour suppressors, kinases, phospahateses and histone-modifying proteins.[2] Two crystal structures of human OGT are reported here, as a binary complex with UDP (2.8 A resolution) and as a ternary complex with UDP and a peptide substrate (1.95 A).
O-GlcNAc transferase Function
The major mechanism for nutrient sensing in eukaryotes involves OGT. OGT senses cellular glucose levels via UDP-GlcNAc concentration, and responds by O-GlcNAcylating a broad range of nuclear anf cytoplasmic proteins.[3] Insulin-like signaling pathways and transcriptional activators that regulate glucose levels by controlling gluconeogenisis include proteins that are O-GlcNAcylated by OGT.[4] Numerous O-GlcNAcylation sites are also phosphorylation sites, OGT is suggested to play a major role in modulating cellular kinase signaling cascades.[5] Widespread transcriptional regulations also involve OGT.[6]
O-GlcNAc Structure
OGT is comprised of two distinct regions: a multidomain catalytic region, which has no available structure and an N-terminal region consistin os a seris of tetratricopeptide repeat(TPR)units.[7] The N terminus of OGT is unusual, consisting of 2.5-13.5 tetratricopeptide repeats (TPRs) depending on alternative splicing.[8] The N-terminal domain of tetratricopeptide (TPR) mediates the recognition of a broad range of target proteins. Components of the nuclear pore complex are major OGT targets, as OGT depletion by RNA interference (RNAi) results in the loss of GlcNAc modification at the nuclear envelope. The crystal structure of the homodimeric TPR domain of human OGT, which contains 11.5 TPR repeats gives insight into the mechanism of target recognition. The repeats form an elongated superhelix. The concave surface of the superhelix is lined by absolutely conserved asparagines, in a manner reminiscent of the peptide-binding site of importin alpha. Based on this structural similarity, it is proposed that OGT uses an analogous molecular mechanism to recognize its targets.[9]
== N Terminus ==
| The crystal structure of the homodimeric TPR domain of human OGT, which contains 11.5 TPR repeats gives insight into the mechanism of target recognition.[10]
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OGT Features of Interest
OGT is the only known member to glycosylate polypeptides and it contains a long uncharacterized intervening sequence (~120 amino acids) in the middle of the catalytic region. Studies suggest that OGT contains a phosphatidylinositol (3,4,5)-trisphosphate (PIP3)binding domain. The most unusual feature of OGT is the intervening domain between the catalytic lobes, which is only found in metazoans. This polypeptide adopts a topologically novel fold with a seven-stranded beta sheet core stabilized by flanking alpha helices. There are two long unstructured loops for which electron density is missing.[11]
O-GlcNAc Modifications
O-GlcNAc modification has been described for a large and still increasing number of proteins, many of which are key modulators of cellular signalling. O-GlcNAc modifications are catalysed by a OGT, and are removed by the antagonistic enzyme B-N-acetylglucosaminidase (O-GlcNAcase). The general scheme of O-linked N-acetylglucosamine modification suggests that N-acetylglucosamine is added to serine/threonine (Ser/Thr) residues of target proteins by the enzyme OGT using UDP-GlcNAc as substrate. The N-acetylglucosamine group is removed by the antagonistic activity of O-GlcNAcase. [12]
Hc and Ganglioside Interaction
References
- ↑ Hart GW, Housley MP, Slawson C. Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature.2007;446:1017-22.[1]
- ↑ Lazarus MB, Nam Y, Jiang J, Sliz P, Walker S. Structure of human O-GlcNAc transferase and its complex with a peptide substrate. Nature. 2011 Jan 27;469(7331):564-7. Epub 2011 Jan 16. PMID:21240259 doi:10.1038/nature09638
- ↑ Hart GW, Housley MP, Slawson C. Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature. 2007 Apr 26;446(7139):1017-22. PMID:17460662 doi:10.1038/nature05815
- ↑ Yang X, Ongusaha PP, Miles PD, Havstad JC, Zhang F, So WV, Kudlow JE, Michell RH, Olefsky JM, Field SJ, Evans RM. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature. 2008 Feb 21;451(7181):964-9. PMID:18288188 doi:10.1038/nature06668
- ↑ Cavill I. Reducing blood transfusion. Focus should be on improving patients' ability to make own blood. BMJ. 2002 Sep 21;325(7365):655. PMID:12269319
- ↑ Gambetta MC, Oktaba K, Muller J. Essential role of the glycosyltransferase sxc/Ogt in polycomb repression. Science. 2009 Jul 3;325(5936):93-6. Epub 2009 May 28. PMID:19478141 doi:10.1126/science.1169727
- ↑ Kreppel LK, Blomberg MA, Hart GW. Dynamic glycosylation of nuclear and cytosolic proteins. Cloning and characterization of a unique O-GlcNAc transferase with multiple tetratricopeptide repeats. J Biol Chem. 1997 Apr 4;272(14):9308-15. PMID:9083067
- ↑ Kreppel L, Hart G. Regulation of a cytosolic and nuclear O-GlcNAc transferase. Role of the tetratricopeptide repeats. J Biol Chem. 1999;274:32015-32022
- ↑ Jinek M, Rehwinkel J, Lazarus BD, Izaurralde E, Hanover JA, Conti E. The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits structural similarities to importin alpha. Nat Struct Mol Biol. 2004 Oct;11(10):1001-7. Epub 2004 Sep 12. PMID:15361863 doi:10.1038/nsmb833
- ↑ Jinek M, Rehwinkel J, Lazarus BD, Izaurralde E, Hanover JA, Conti E. The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits structural similarities to importin alpha. Nat Struct Mol Biol. 2004 Oct;11(10):1001-7. Epub 2004 Sep 12. PMID:15361863 doi:10.1038/nsmb833
- ↑ Yang X, Ongusaha PP, Miles PD, Havstad JC, Zhang F, So WV, Kudlow JE, Michell RH, Olefsky JM, Field SJ, Evans RM. Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance. Nature. 2008 Feb 21;451(7181):964-9. PMID:18288188 doi:10.1038/nature06668
- ↑ Alexander G, Danilo G. The O-linked N-acetylglucosamine modification in cellular signalling and the immune system. EMBO reports. 2008 June;9:748-753[2]
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