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| | <StructureSection load='6pxu' size='340' side='right'caption='[[6pxu]], [[Resolution|resolution]] 2.01Å' scene=''> | | <StructureSection load='6pxu' size='340' side='right'caption='[[6pxu]], [[Resolution|resolution]] 2.01Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6pxu]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PXU OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PXU FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6pxu]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PXU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PXU FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=A2G:N-ACETYL-2-DEOXY-2-AMINO-GALACTOSE'>A2G</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</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]] 2.007Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GALNT12 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A2G:N-ACETYL-2-DEOXY-2-AMINO-GALACTOSE'>A2G</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Polypeptide_N-acetylgalactosaminyltransferase Polypeptide N-acetylgalactosaminyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.4.1.41 2.4.1.41] </span></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=6pxu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pxu OCA], [https://pdbe.org/6pxu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pxu RCSB], [https://www.ebi.ac.uk/pdbsum/6pxu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pxu ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6pxu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pxu OCA], [http://pdbe.org/6pxu PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pxu RCSB], [http://www.ebi.ac.uk/pdbsum/6pxu PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pxu ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/GLT12_HUMAN GLT12_HUMAN]] Disease susceptibility is associated with variations affecting the gene represented in this entry. The role of GALNT12 in colon cancer susceptibility is however subject to discussion: studies on 103 probants with colorectal cancer 1 (CRCS1) suggest that it does not act as a major contributor of CRCS1 (PubMed:24115450).<ref>PMID:24115450</ref> | + | [https://www.uniprot.org/uniprot/GLT12_HUMAN GLT12_HUMAN] Disease susceptibility is associated with variations affecting the gene represented in this entry. The role of GALNT12 in colon cancer susceptibility is however subject to discussion: studies on 103 probants with colorectal cancer 1 (CRCS1) suggest that it does not act as a major contributor of CRCS1 (PubMed:24115450).<ref>PMID:24115450</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/GLT12_HUMAN GLT12_HUMAN]] Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Has activity toward non-glycosylated peptides such as Muc5AC, Muc1a and EA2, and no detectable activity with Muc2 and Muc7. Displays enzymatic activity toward the Gal-NAc-Muc5AC glycopeptide, but no detectable activity to mono-GalNAc-glycosylated Muc1a, Muc2, Muc7 and EA2. May play an important role in the initial step of mucin-type oligosaccharide biosynthesis in digestive organs. | + | [https://www.uniprot.org/uniprot/GLT12_HUMAN GLT12_HUMAN] Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Has activity toward non-glycosylated peptides such as Muc5AC, Muc1a and EA2, and no detectable activity with Muc2 and Muc7. Displays enzymatic activity toward the Gal-NAc-Muc5AC glycopeptide, but no detectable activity to mono-GalNAc-glycosylated Muc1a, Muc2, Muc7 and EA2. May play an important role in the initial step of mucin-type oligosaccharide biosynthesis in digestive organs. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Polypeptide N-acetylgalactosaminyltransferase]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Fernandez, A J]] | + | [[Category: Fernandez AJ]] |
| - | [[Category: Samara, N L]] | + | [[Category: Samara NL]] |
| - | [[Category: Colorectal cancer]]
| + | |
| - | [[Category: Crc]]
| + | |
| - | [[Category: Enzyme catalysis]]
| + | |
| - | [[Category: Galnac-t]]
| + | |
| - | [[Category: Mucin-type o-glycosylation]]
| + | |
| - | [[Category: Substrate selectivity]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
6pxu is a 4 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | X-ray diffraction, Resolution 2.007Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
GLT12_HUMAN Disease susceptibility is associated with variations affecting the gene represented in this entry. The role of GALNT12 in colon cancer susceptibility is however subject to discussion: studies on 103 probants with colorectal cancer 1 (CRCS1) suggest that it does not act as a major contributor of CRCS1 (PubMed:24115450).[1]
Function
GLT12_HUMAN Catalyzes the initial reaction in O-linked oligosaccharide biosynthesis, the transfer of an N-acetyl-D-galactosamine residue to a serine or threonine residue on the protein receptor. Has activity toward non-glycosylated peptides such as Muc5AC, Muc1a and EA2, and no detectable activity with Muc2 and Muc7. Displays enzymatic activity toward the Gal-NAc-Muc5AC glycopeptide, but no detectable activity to mono-GalNAc-glycosylated Muc1a, Muc2, Muc7 and EA2. May play an important role in the initial step of mucin-type oligosaccharide biosynthesis in digestive organs.
Publication Abstract from PubMed
Polypeptide N-acetylgalactosaminyl transferases (GalNAc-Ts) initiate mucin type O-glycosylation by catalyzing the transfer of N-acetylgalactosamine (GalNAc) to Ser or Thr on a protein substrate. Inactive and partially active variants of the isoenzyme GalNAc-T12 are present in subsets of patients with colorectal cancer, and several of these variants alter nonconserved residues with unknown functions. While previous biochemical studies have demonstrated that GalNAc-T12 selects for peptide and glycopeptide substrates through unique interactions with its catalytic and lectin domains, the molecular basis for this distinct substrate selectivity remains elusive. Here we examine the molecular basis of the activity and substrate selectivity of GalNAc-T12. The X-ray crystal structure of GalNAc-T12 in complex with a di-glycosylated peptide substrate reveals how a nonconserved GalNAc binding pocket in the GalNAc-T12 catalytic domain dictates its unique substrate selectivity. In addition, the structure provides insight into how colorectal cancer mutations disrupt the activity of GalNAc-T12 and illustrates how the rules dictating GalNAc-T12 function are distinct from those for other GalNAc-Ts.
The structure of the colorectal cancer-associated enzyme GalNAc-T12 reveals how nonconserved residues dictate its function.,Fernandez AJ, Daniel EJP, Mahajan SP, Gray JJ, Gerken TA, Tabak LA, Samara NL Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20404-20410. doi:, 10.1073/pnas.1902211116. Epub 2019 Sep 23. PMID:31548401[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Segui N, Pineda M, Navarro M, Lazaro C, Brunet J, Infante M, Duran M, Soto JL, Blanco I, Capella G, Valle L. GALNT12 is not a major contributor of familial colorectal cancer type X. Hum Mutat. 2014 Jan;35(1):50-2. doi: 10.1002/humu.22454. Epub 2013 Oct 17. PMID:24115450 doi:http://dx.doi.org/10.1002/humu.22454
- ↑ Fernandez AJ, Daniel EJP, Mahajan SP, Gray JJ, Gerken TA, Tabak LA, Samara NL. The structure of the colorectal cancer-associated enzyme GalNAc-T12 reveals how nonconserved residues dictate its function. Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20404-20410. doi:, 10.1073/pnas.1902211116. Epub 2019 Sep 23. PMID:31548401 doi:http://dx.doi.org/10.1073/pnas.1902211116
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