Sandbox Reserved 381: Difference between revisions
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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.<ref> Hart GW, Housley MP, Slawson C. Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature.2007;446:1017-22.[http://www.nature.com/nature/journal/v446/n7139/abs/nature05815.html]</ref> 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.<ref>PMID:21240259</ref> 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-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.<ref> Hart GW, Housley MP, Slawson C. Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins. Nature.2007;446:1017-22.[http://www.nature.com/nature/journal/v446/n7139/abs/nature05815.html]</ref> 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.<ref>PMID:21240259</ref> 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.<ref> Insulin-like signaling pathways and transcriptional activators that regulate glucose levels by controlling gluconeogenisis include proteins that are O-GlcNAcylated by OGT.<ref> Numerous O-GlcNAcylation sites are also phosphorylation sites, OGT is suggested to play a major role in modulating cellular kinase signaling cascades.<ref> Widespread transcriptional regulations also involve OGT.<ref> | |||
== 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.<refThe N terminus of OGT is unusual, consisting of 2.5-13.5 tetratricopeptide repeats (TPRs) depending on alternative splicing.<ref>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</ref> 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.<ref>PMID:15361863</ref> | |||
== N Terminus == | |||
(Superhelical TPR Domain of O-Linked GlcNAc Transferase)<StructureSection load='1w3b' size='300' side='right' caption='Structure of HMG-CoA reductase (PDB entry [[1w3b]])' scene=''> </StructureSection> | |||
== O-GlcNAc Modifications == | == 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 | 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. <ref>Alexander G, Danilo G. The O-linked N-acetylglucosamine modification in cellular signalling and the immune system. EMBO reports. 2008 June;9:748-753[http://www.nature.com/embor/journal/v9/n8/full/embor2008129.html]</ref> | ||
== Tetanospasmin (TeNT) == | == Tetanospasmin (TeNT) == | ||
