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| | <StructureSection load='5ky4' size='340' side='right'caption='[[5ky4]], [[Resolution|resolution]] 1.47Å' scene=''> | | <StructureSection load='5ky4' size='340' side='right'caption='[[5ky4]], [[Resolution|resolution]] 1.47Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5ky4]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KY4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5KY4 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5ky4]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KY4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5KY4 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PGO:S-1,2-PROPANEDIOL'>PGO</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.472Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5kxh|5kxh]], [[5kxq|5kxq]], [[5ky0|5ky0]], [[5ky2|5ky2]], [[5ky3|5ky3]], [[5ky5|5ky5]], [[5ky7|5ky7]], [[5ky8|5ky8]], [[5ky9|5ky9]]</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=PGO:S-1,2-PROPANEDIOL'>PGO</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Pofut1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice]), Notch1, Motch ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ky4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ky4 OCA], [https://pdbe.org/5ky4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ky4 RCSB], [https://www.ebi.ac.uk/pdbsum/5ky4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ky4 ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptide-O-fucosyltransferase Peptide-O-fucosyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.1.221 2.4.1.221] </span></td></tr> | + | |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5ky4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ky4 OCA], [http://pdbe.org/5ky4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ky4 RCSB], [http://www.ebi.ac.uk/pdbsum/5ky4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ky4 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/OFUT1_MOUSE OFUT1_MOUSE]] Catalyzes the reaction that attaches fucose through an O-glycosidic linkage to a conserved serine or threonine residue found in the consensus sequence C2-X(4,5)-[S/T]-C3 of EGF domains, where C2 and C3 are the second and third conserved cysteines. Specifically uses GDP-fucose as donor substrate and proper disulfide pairing of the substrate EGF domains is required for fucose transfer. Plays a crucial role in NOTCH signaling. Initial fucosylation of NOTCH by POFUT1 generates a substrate for FRINGE/RFNG, an acetylglucosaminyltransferase that can then extend the fucosylation on the NOTCH EGF repeats. This extended fucosylation is required for optimal ligand binding and canonical NOTCH signaling induced by DLL1 or JAGGED1. Fucosylates AGRN and determines its ability to cluster acetylcholine receptors (AChRs).<ref>PMID:12697902</ref> <ref>PMID:18775496</ref> [[http://www.uniprot.org/uniprot/NOTC1_MOUSE NOTC1_MOUSE]] Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Involved in the maturation of both CD4+ and CD8+ cells in the thymus. Important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation. May be involved in mesoderm development, somite formation and neurogenesis. May enhance HIF1A function by sequestering HIF1AN away from HIF1A. Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury. Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO).<ref>PMID:15965470</ref> <ref>PMID:18299578</ref> <ref>PMID:23160044</ref> <ref>PMID:23615612</ref> | + | [https://www.uniprot.org/uniprot/OFUT1_MOUSE OFUT1_MOUSE] Catalyzes the reaction that attaches fucose through an O-glycosidic linkage to a conserved serine or threonine residue found in the consensus sequence C2-X(4,5)-[S/T]-C3 of EGF domains, where C2 and C3 are the second and third conserved cysteines. Specifically uses GDP-fucose as donor substrate and proper disulfide pairing of the substrate EGF domains is required for fucose transfer. Plays a crucial role in NOTCH signaling. Initial fucosylation of NOTCH by POFUT1 generates a substrate for FRINGE/RFNG, an acetylglucosaminyltransferase that can then extend the fucosylation on the NOTCH EGF repeats. This extended fucosylation is required for optimal ligand binding and canonical NOTCH signaling induced by DLL1 or JAGGED1. Fucosylates AGRN and determines its ability to cluster acetylcholine receptors (AChRs).<ref>PMID:12697902</ref> <ref>PMID:18775496</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Peptide-O-fucosyltransferase]]
| + | [[Category: Li Z]] |
| - | [[Category: Li, Z]] | + | [[Category: Rini JM]] |
| - | [[Category: Rini, J M]] | + | |
| - | [[Category: Glycosyltransferase]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
OFUT1_MOUSE Catalyzes the reaction that attaches fucose through an O-glycosidic linkage to a conserved serine or threonine residue found in the consensus sequence C2-X(4,5)-[S/T]-C3 of EGF domains, where C2 and C3 are the second and third conserved cysteines. Specifically uses GDP-fucose as donor substrate and proper disulfide pairing of the substrate EGF domains is required for fucose transfer. Plays a crucial role in NOTCH signaling. Initial fucosylation of NOTCH by POFUT1 generates a substrate for FRINGE/RFNG, an acetylglucosaminyltransferase that can then extend the fucosylation on the NOTCH EGF repeats. This extended fucosylation is required for optimal ligand binding and canonical NOTCH signaling induced by DLL1 or JAGGED1. Fucosylates AGRN and determines its ability to cluster acetylcholine receptors (AChRs).[1] [2]
Publication Abstract from PubMed
Protein O-fucosyltransferase 1 (POFUT1) fucosylates the epidermal growth factor (EGF)-like domains found in cell-surface and secreted glycoproteins including Notch and its ligands. Although Notch fucosylation is critical for development, and POFUT1 deficiency leads to human disease, how this enzyme binds and catalyzes the fucosylation of its diverse EGF-like domain substrates has not been determined. Reported here is the X-ray crystal structure of mouse POFUT1 in complex with several EGF-like domains, including EGF12 and EGF26 of Notch. Overall shape complementarity, interactions with invariant atoms of the fucosylation motif and flexible segments on POFUT1 all define its EGF-like-domain binding properties. Using large-scale structural and sequence analysis, we also show that POFUT1 binds EGF-like domains of the hEGF type and that the highly correlated presence of POFUT1 and fucosylatable hEGFs has accompanied animal evolution.
Recognition of EGF-like domains by the Notch-modifying O-fucosyltransferase POFUT1.,Li Z, Han K, Pak JE, Satkunarajah M, Zhou D, Rini JM Nat Chem Biol. 2017 Jul;13(7):757-763. doi: 10.1038/nchembio.2381. Epub 2017 May , 22. PMID:28530709[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Shi S, Stanley P. Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways. Proc Natl Acad Sci U S A. 2003 Apr 29;100(9):5234-9. Epub 2003 Apr 15. PMID:12697902 doi:http://dx.doi.org/10.1073/pnas.0831126100
- ↑ Kim ML, Chandrasekharan K, Glass M, Shi S, Stahl MC, Kaspar B, Stanley P, Martin PT. O-fucosylation of muscle agrin determines its ability to cluster acetylcholine receptors. Mol Cell Neurosci. 2008 Nov;39(3):452-64. doi: 10.1016/j.mcn.2008.07.026. Epub, 2008 Aug 15. PMID:18775496 doi:http://dx.doi.org/10.1016/j.mcn.2008.07.026
- ↑ Li Z, Han K, Pak JE, Satkunarajah M, Zhou D, Rini JM. Recognition of EGF-like domains by the Notch-modifying O-fucosyltransferase POFUT1. Nat Chem Biol. 2017 Jul;13(7):757-763. doi: 10.1038/nchembio.2381. Epub 2017 May , 22. PMID:28530709 doi:http://dx.doi.org/10.1038/nchembio.2381
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