6s22

From Proteopedia

(Difference between revisions)

Revision as of 16:50, 22 January 2020

Crystal structure of the TgGalNAc-T3 in complex with UDP, manganese and FGF23c

Structural highlights

6s22 is a 2 chain structure with sequence from Poephila guttata. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , , , ,
Gene:	GALNT3 (Poephila guttata)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[FGF23_HUMAN] Defects in FGF23 are the cause of autosomal dominant hypophosphataemic rickets (ADHR) [MIM:193100]. ADHR is characterized by low serum phosphorus concentrations, rickets, osteomalacia, leg deformities, short stature, bone pain and dental abscesses.^[1] ^[2] ^[3] Defects in FGF23 are a cause of hyperphosphatemic familial tumoral calcinosis (HFTC) [MIM:211900]. HFTC is a severe autosomal recessive metabolic disorder that manifests with hyperphosphatemia and massive calcium deposits in the skin and subcutaneous tissues.^[4]

Function

[FGF23_HUMAN] Regulator of phosphate homeostasis. Inhibits renal tubular phosphate transport by reducing SLC34A1 levels. Upregulates EGR1 expression in the presence of KL (By similarity). Acts directly on the parathyroid to decrease PTH secretion (By similarity). Regulator of vitamin-D metabolism. Negatively regulates osteoblast differentiation and matrix mineralization.^[5] ^[6] ^[7] ^[8] ^[9]

Publication Abstract from PubMed

Polypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif RHT(178)R downward arrowS. FGF23 regulates phosphate homeostasis and deficiency in GALNT3 or FGF23 results in hyperphosphatemia and familial tumoral calcinosis. We explored the molecular mechanism for GalNAc-T3 glycosylation of FGF23 using engineered cell models and biophysical studies including kinetics, molecular dynamics and X-ray crystallography of GalNAc-T3 complexed to glycopeptide substrates. GalNAc-T3 uses a lectin domain mediated mechanism to glycosylate Thr178 requiring previous glycosylation at Thr171. Notably, Thr178 is a poor substrate site with limiting glycosylation due to substrate clashes leading to destabilization of the catalytic domain flexible loop. We suggest GalNAc-T3 specificity for FGF23 and its ability to control circulating levels of intact FGF23 is achieved by FGF23 being a poor substrate. GalNAc-T3's structure further reveals the molecular bases for reported disease-causing mutations. Our findings provide an insight into how GalNAc-T isoenzymes achieve isoenzyme-specific nonredundant functions.

Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3.,de Las Rivas M, Paul Daniel EJ, Narimatsu Y, Companon I, Kato K, Hermosilla P, Thureau A, Ceballos-Laita L, Coelho H, Bernado P, Marcelo F, Hansen L, Maeda R, Lostao A, Corzana F, Clausen H, Gerken TA, Hurtado-Guerrero R Nat Chem Biol. 2020 Jan 13. pii: 10.1038/s41589-019-0444-x. doi:, 10.1038/s41589-019-0444-x. PMID:31932717^[10]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ . Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000 Nov;26(3):345-8. PMID:11062477 doi:10.1038/81664
↑ Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine MA, Kumar R, Schiavi SC. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun. 2001 Jun 22;284(4):977-81. PMID:11409890 doi:10.1006/bbrc.2001.5084
↑ Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP, Mandel U, Strom TM, Clausen H. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem. 2006 Jul 7;281(27):18370-7. Epub 2006 Apr 25. PMID:16638743 doi:10.1074/jbc.M602469200
↑ Benet-Pages A, Orlik P, Strom TM, Lorenz-Depiereux B. An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet. 2005 Feb 1;14(3):385-90. Epub 2004 Dec 8. PMID:15590700 doi:10.1093/hmg/ddi034
↑ . Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000 Nov;26(3):345-8. PMID:11062477 doi:10.1038/81664
↑ Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine MA, Kumar R, Schiavi SC. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun. 2001 Jun 22;284(4):977-81. PMID:11409890 doi:10.1006/bbrc.2001.5084
↑ Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004 Mar;19(3):429-35. Epub 2003 Dec 29. PMID:15040831 doi:10.1359/JBMR.0301264
↑ Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM. Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem. 2006 Jun 9;281(23):15694-700. Epub 2006 Apr 4. PMID:16597617 doi:10.1074/jbc.M601252200
↑ Wang H, Yoshiko Y, Yamamoto R, Minamizaki T, Kozai K, Tanne K, Aubin JE, Maeda N. Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro. J Bone Miner Res. 2008 Jun;23(6):939-48. doi: 10.1359/jbmr.080220. PMID:18282132 doi:10.1359/jbmr.080220
↑ de Las Rivas M, Paul Daniel EJ, Narimatsu Y, Companon I, Kato K, Hermosilla P, Thureau A, Ceballos-Laita L, Coelho H, Bernado P, Marcelo F, Hansen L, Maeda R, Lostao A, Corzana F, Clausen H, Gerken TA, Hurtado-Guerrero R. Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3. Nat Chem Biol. 2020 Jan 13. pii: 10.1038/s41589-019-0444-x. doi:, 10.1038/s41589-019-0444-x. PMID:31932717 doi:http://dx.doi.org/10.1038/s41589-019-0444-x

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6s22"

@@ Line 3: / Line 3: @@
 <StructureSection load='6s22' size='340' side='right'caption='[[6s22]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6s22]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6S22 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6S22 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6s22]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Poephila_guttata Poephila guttata]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6S22 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6S22 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NGA:N-ACETYL-D-GALACTOSAMINE'>NGA</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=UDP:URIDINE-5-DIPHOSPHATE'>UDP</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GALNT3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=59729 Poephila guttata])</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=6s22 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6s22 OCA], [http://pdbe.org/6s22 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6s22 RCSB], [http://www.ebi.ac.uk/pdbsum/6s22 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6s22 ProSAT]</span></td></tr>
 </table>
@@ Line 11: / Line 12: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/FGF23_HUMAN FGF23_HUMAN]] Regulator of phosphate homeostasis. Inhibits renal tubular phosphate transport by reducing SLC34A1 levels. Upregulates EGR1 expression in the presence of KL (By similarity). Acts directly on the parathyroid to decrease PTH secretion (By similarity). Regulator of vitamin-D metabolism. Negatively regulates osteoblast differentiation and matrix mineralization.<ref>PMID:11062477</ref> <ref>PMID:11409890</ref> <ref>PMID:15040831</ref> <ref>PMID:16597617</ref> <ref>PMID:18282132</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Polypeptide GalNAc-transferase T3 (GalNAc-T3) regulates fibroblast growth factor 23 (FGF23) by O-glycosylating Thr178 in a furin proprotein processing motif RHT(178)R downward arrowS. FGF23 regulates phosphate homeostasis and deficiency in GALNT3 or FGF23 results in hyperphosphatemia and familial tumoral calcinosis. We explored the molecular mechanism for GalNAc-T3 glycosylation of FGF23 using engineered cell models and biophysical studies including kinetics, molecular dynamics and X-ray crystallography of GalNAc-T3 complexed to glycopeptide substrates. GalNAc-T3 uses a lectin domain mediated mechanism to glycosylate Thr178 requiring previous glycosylation at Thr171. Notably, Thr178 is a poor substrate site with limiting glycosylation due to substrate clashes leading to destabilization of the catalytic domain flexible loop. We suggest GalNAc-T3 specificity for FGF23 and its ability to control circulating levels of intact FGF23 is achieved by FGF23 being a poor substrate. GalNAc-T3's structure further reveals the molecular bases for reported disease-causing mutations. Our findings provide an insight into how GalNAc-T isoenzymes achieve isoenzyme-specific nonredundant functions.
+Molecular basis for fibroblast growth factor 23 O-glycosylation by GalNAc-T3.,de Las Rivas M, Paul Daniel EJ, Narimatsu Y, Companon I, Kato K, Hermosilla P, Thureau A, Ceballos-Laita L, Coelho H, Bernado P, Marcelo F, Hansen L, Maeda R, Lostao A, Corzana F, Clausen H, Gerken TA, Hurtado-Guerrero R Nat Chem Biol. 2020 Jan 13. pii: 10.1038/s41589-019-0444-x. doi:, 10.1038/s41589-019-0444-x. PMID:31932717<ref>PMID:31932717</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6s22" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
@@ Line 16: / Line 26: @@
 </StructureSection>
 [[Category: Large Structures]]
+[[Category: Poephila guttata]]
 [[Category: Bernado, P]]
 [[Category: Ceballos-Laita, L]]

6s22

From Proteopedia

Revision as of 16:50, 22 January 2020

Crystal structure of the TgGalNAc-T3 in complex with UDP, manganese and FGF23c

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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