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| | ==Alanine-glyoxylate aminotransferase variant K390A in complex with the TPR domain of human Pex5p== | | ==Alanine-glyoxylate aminotransferase variant K390A in complex with the TPR domain of human Pex5p== |
| - | <StructureSection load='4kyo' size='340' side='right' caption='[[4kyo]], [[Resolution|resolution]] 2.20Å' scene=''> | + | <StructureSection load='4kyo' size='340' side='right'caption='[[4kyo]], [[Resolution|resolution]] 2.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4kyo]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KYO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4KYO FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4kyo]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4KYO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4KYO FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=BTB:2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>BTB</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3r9a|3r9a]], [[4kxk|4kxk]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=BTB:2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>BTB</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=4kyo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kyo OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4kyo RCSB], [http://www.ebi.ac.uk/pdbsum/4kyo PDBsum]</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=4kyo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4kyo OCA], [https://pdbe.org/4kyo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4kyo RCSB], [https://www.ebi.ac.uk/pdbsum/4kyo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4kyo ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/SPYA_HUMAN SPYA_HUMAN]] Defects in AGXT are the cause of hyperoxaluria primary type 1 (HP1) [MIM:[http://omim.org/entry/259900 259900]]; also known as primary hyperoxaluria type I (PH1) and oxalosis I. HP1 is a rare autosomal recessive inborn error of glyoxylate metabolism characterized by increased excretion of oxalate and glycolate, and the progressive accumulation of insoluble calcium oxalate in the kidney and urinary tract.<ref>PMID:1703535</ref> <ref>PMID:2039493</ref> <ref>PMID:1349575</ref> <ref>PMID:1301173</ref> <ref>PMID:8101040</ref> <ref>PMID:9192270</ref> <ref>PMID:9604803</ref> <ref>PMID:10394939</ref> <ref>PMID:10453743</ref> <ref>PMID:10541294</ref> <ref>PMID:10862087</ref> <ref>PMID:10960483</ref> <ref>PMID:12559847</ref> <ref>PMID:12777626</ref> <ref>PMID:15253729</ref> <ref>PMID:15849466</ref> <ref>PMID:15961946</ref> <ref>PMID:15963748</ref> [[http://www.uniprot.org/uniprot/PEX5_HUMAN PEX5_HUMAN]] Defects in PEX5 are the cause of peroxisome biogenesis disorder 2A (PBD2A) [MIM:[http://omim.org/entry/214110 214110]]. A fatal peroxisome biogenesis disorder belonging to the Zellweger disease spectrum and characterized clinically by severe neurologic dysfunction with profound psychomotor retardation, severe hypotonia and neonatal seizures, craniofacial abnormalities, liver dysfunction, and biochemically by the absence of peroxisomes. Additional features include cardiovascular and skeletal defects, renal cysts, ocular abnormalities, and hearing impairment. Most severely affected individuals with the classic form of the disease (classic Zellweger syndrome) die within the first year of life.<ref>PMID:7719337</ref> Defects in PEX5 are the cause of peroxisome biogenesis disorder 2B (PBD2B) [MIM:[http://omim.org/entry/202370 202370]]. A peroxisome biogenesis disorder that includes neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), two milder manifestations of the Zellweger disease spectrum. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy and vision impairment. Children with the NALD presentation may reach their teens, while patients with the IRD presentation may reach adulthood. The clinical conditions are often slowly progressive in particular with respect to loss of hearing and vision. The biochemical abnormalities include accumulation of phytanic acid, very long chain fatty acids (VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid. | + | [https://www.uniprot.org/uniprot/AGT1_HUMAN AGT1_HUMAN] Primary hyperoxaluria type 1. The disease is caused by variants affecting the gene represented in this entry. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PEX5_HUMAN PEX5_HUMAN]] Binds to the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) and plays an essential role in peroxisomal protein import.<ref>PMID:7719337</ref> <ref>PMID:7790377</ref> <ref>PMID:7706321</ref> | + | [https://www.uniprot.org/uniprot/AGT1_HUMAN AGT1_HUMAN] Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification (PubMed:10960483, PubMed:12777626, PubMed:24055001, PubMed:23229545, PubMed:26149463). Also catalyzes the transamination between L-serine and pyruvate and contributes to gluconeogenesis from the L-serine metabolism (PubMed:10347152).<ref>PMID:10347152</ref> <ref>PMID:10960483</ref> <ref>PMID:12777626</ref> <ref>PMID:23229545</ref> <ref>PMID:24055001</ref> <ref>PMID:26149463</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4kyo" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Aminotransferase 3D structures|Aminotransferase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Fodor, K]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Lou, Y]] | + | [[Category: Large Structures]] |
| - | [[Category: Wilmanns, M]] | + | [[Category: Fodor K]] |
| - | [[Category: Aminotransferase]] | + | [[Category: Lou Y]] |
| - | [[Category: Peroxisomal import]] | + | [[Category: Wilmanns M]] |
| - | [[Category: Peroxisome]]
| + | |
| - | [[Category: Primary hyperoxaluria]]
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| - | [[Category: Pyruvate]]
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| - | [[Category: Tpr-domain]]
| + | |
| - | [[Category: Transferase-transport protein complex]]
| + | |
| - | [[Category: Transport]]
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| Structural highlights
Disease
AGT1_HUMAN Primary hyperoxaluria type 1. The disease is caused by variants affecting the gene represented in this entry.
Function
AGT1_HUMAN Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification (PubMed:10960483, PubMed:12777626, PubMed:24055001, PubMed:23229545, PubMed:26149463). Also catalyzes the transamination between L-serine and pyruvate and contributes to gluconeogenesis from the L-serine metabolism (PubMed:10347152).[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Peroxisomes entirely rely on the import of their proteome across the peroxisomal membrane. Recognition efficiencies of peroxisomal proteins vary by more than 1000-fold but the molecular rationale behind their subsequent differential import and sorting has remained enigmatic. Using the protein cargo alanine-glyoxylate aminotransferase as a model, we have discovered an unexpected increase from 34% to 80% in peroxisomal import efficiency of a single-residue mutant. By high-resolution structural analysis, we found that it is the recognition receptor PEX5 that adapts its conformation for high-affinity binding rather than the cargo protein signal motif as previously thought. During receptor recognition, the binding cavity of the receptor shrinks to one third of its original volume. This process is impeded in the wild-type protein cargo because of a bulky side chain within the recognition motif, which blocks contraction of the PEX5 binding cavity. Our data provide a new insight on direct protein import efficiency by removal rather than addition of an apparent specific sequence signature that is generally applicable to peroxisomal matrix proteins and to other receptor recognition processes.
Ligand-induced compaction of the PEX5 receptor-binding cavity impacts protein import efficiency into peroxisomes.,Fodor K, Wolf J, Reglinski K, Passon DM, Lou Y, Schliebs W, Erdmann R, Wilmanns M Traffic. 2014 Nov 5. doi: 10.1111/tra.12238. PMID:25369882[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Xue HH, Sakaguchi T, Fujie M, Ogawa H, Ichiyama A. Flux of the L-serine metabolism in rabbit, human, and dog livers. Substantial contributions of both mitochondrial and peroxisomal serine:pyruvate/alanine:glyoxylate aminotransferase. J Biol Chem. 1999 Jun 4;274(23):16028-33. doi: 10.1074/jbc.274.23.16028. PMID:10347152 doi:http://dx.doi.org/10.1074/jbc.274.23.16028
- ↑ Lumb MJ, Danpure CJ. Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations. J Biol Chem. 2000 Nov 17;275(46):36415-22. PMID:10960483 doi:10.1074/jbc.M006693200
- ↑ Santana A, Salido E, Torres A, Shapiro LJ. Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7277-82. Epub 2003 May 30. PMID:12777626 doi:10.1073/pnas.1131968100
- ↑ Fargue S, Lewin J, Rumsby G, Danpure CJ. Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele. J Biol Chem. 2013 Jan 25;288(4):2475-84. doi: 10.1074/jbc.M112.432617. Epub 2012 , Dec 10. PMID:23229545 doi:http://dx.doi.org/10.1074/jbc.M112.432617
- ↑ Oppici E, Roncador A, Montioli R, Bianconi S, Cellini B. Gly161 mutations associated with Primary Hyperoxaluria Type I induce the cytosolic aggregation and the intracellular degradation of the apo-form of alanine:glyoxylate aminotransferase. Biochim Biophys Acta. 2013 Dec;1832(12):2277-88. doi:, 10.1016/j.bbadis.2013.09.002. Epub 2013 Sep 17. PMID:24055001 doi:http://dx.doi.org/10.1016/j.bbadis.2013.09.002
- ↑ Montioli R, Oppici E, Dindo M, Roncador A, Gotte G, Cellini B, Borri Voltattorni C. Misfolding caused by the pathogenic mutation G47R on the minor allele of alanine:glyoxylate aminotransferase and chaperoning activity of pyridoxine. Biochim Biophys Acta. 2015 Oct;1854(10 Pt A):1280-9. doi:, 10.1016/j.bbapap.2015.07.002. Epub 2015 Jul 3. PMID:26149463 doi:http://dx.doi.org/10.1016/j.bbapap.2015.07.002
- ↑ Fodor K, Wolf J, Reglinski K, Passon DM, Lou Y, Schliebs W, Erdmann R, Wilmanns M. Ligand-induced compaction of the PEX5 receptor-binding cavity impacts protein import efficiency into peroxisomes. Traffic. 2014 Nov 5. doi: 10.1111/tra.12238. PMID:25369882 doi:http://dx.doi.org/10.1111/tra.12238
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