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6zk7

From Proteopedia

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Current revision

Crystal Structure of human PYROXD1/FAD complex

Structural highlights

6zk7 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.2Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PYRD1_HUMAN The disease is caused by variants affecting the gene represented in this entry. A mutation in PYROXD1 is the cause of autosomal recessive limb-girdle muscular dystrophy. The affected individual with a homozygous recessive PYROXD1 mutation showed progressive muscle weakness with an onset at the age of 9 years. Initial symptoms included excessive falling while running, with slowly progressive weakness. Difficulty navigating stairs by the age if 18, and loss of ambulation at the age of 37 years. Neurological examination showed proximal symmetrical muscle weakness and wasting, along with calf muscle pseudohypertrophy.^[1]

Function

PYRD1_HUMAN Probable FAD-dependent oxidoreductase; involved in the cellular oxidative stress response (PubMed:27745833). Required for normal sarcomere structure and muscle fiber integrity (By similarity).[UniProtKB:Q6PBT5]^[2]

Publication Abstract from PubMed

The tRNA ligase complex (tRNA-LC) splices precursor tRNAs (pre-tRNA), and Xbp1-mRNA during the unfolded protein response (UPR). In aerobic conditions, a cysteine residue bound to two metal ions in its ancient, catalytic subunit RTCB could make the tRNA-LC susceptible to oxidative inactivation. Here, we confirm this hypothesis and reveal a co-evolutionary association between the tRNA-LC and PYROXD1, a conserved and essential oxidoreductase. We reveal that PYROXD1 preserves the activity of the mammalian tRNA-LC in pre-tRNA splicing and UPR. PYROXD1 binds the tRNA-LC in the presence of NAD(P)H and converts RTCB-bound NAD(P)H into NAD(P)(+), a typical oxidative co-enzyme. However, NAD(P)(+) here acts as an antioxidant and protects the tRNA-LC from oxidative inactivation, which is dependent on copper ions. Genetic variants of PYROXD1 that cause human myopathies only partially support tRNA-LC activity. Thus, we establish the tRNA-LC as an oxidation-sensitive metalloenzyme, safeguarded by the flavoprotein PYROXD1 through an unexpected redox mechanism.

The oxidoreductase PYROXD1 uses NAD(P)(+) as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response.,Asanovic I, Strandback E, Kroupova A, Pasajlic D, Meinhart A, Tsung-Pin P, Djokovic N, Anrather D, Schuetz T, Suskiewicz MJ, Sillamaa S, Kocher T, Beveridge R, Nikolic K, Schleiffer A, Jinek M, Hartl M, Clausen T, Penninger J, Macheroux P, Weitzer S, Martinez J Mol Cell. 2021 Apr 23. pii: S1097-2765(21)00312-9. doi:, 10.1016/j.molcel.2021.04.007. PMID:33930333^[3]

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

References

↑ Saha M, Reddy HM, Salih MA, Estrella E, Jones MD, Mitsuhashi S, Cho KA, Suzuki-Hatano S, Rizzo SA, Hamad MH, Mukhtar MM, Hamed AA, Elseed MA, Lek M, Valkanas E, MacArthur DG, Kunkel LM, Pacak CA, Draper I, Kang PB. Impact of PYROXD1 deficiency on cellular respiration and correlations with genetic analyses of limb-girdle muscular dystrophy in Saudi Arabia and Sudan. Physiol Genomics. 2018 Nov 1;50(11):929-939. doi:, 10.1152/physiolgenomics.00036.2018. Epub 2018 Aug 31. PMID:30345904 doi:http://dx.doi.org/10.1152/physiolgenomics.00036.2018
↑ O'Grady GL, Best HA, Sztal TE, Schartner V, Sanjuan-Vazquez M, Donkervoort S, Abath Neto O, Sutton RB, Ilkovski B, Romero NB, Stojkovic T, Dastgir J, Waddell LB, Boland A, Hu Y, Williams C, Ruparelia AA, Maisonobe T, Peduto AJ, Reddel SW, Lek M, Tukiainen T, Cummings BB, Joshi H, Nectoux J, Brammah S, Deleuze JF, Ing VO, Ramm G, Ardicli D, Nowak KJ, Talim B, Topaloglu H, Laing NG, North KN, MacArthur DG, Friant S, Clarke NF, Bryson-Richardson RJ, Bonnemann CG, Laporte J, Cooper ST. Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization. Am J Hum Genet. 2016 Nov 3;99(5):1086-1105. doi: 10.1016/j.ajhg.2016.09.005. Epub, 2016 Oct 13. PMID:27745833 doi:http://dx.doi.org/10.1016/j.ajhg.2016.09.005
↑ Asanovic I, Strandback E, Kroupova A, Pasajlic D, Meinhart A, Tsung-Pin P, Djokovic N, Anrather D, Schuetz T, Suskiewicz MJ, Sillamaa S, Kocher T, Beveridge R, Nikolic K, Schleiffer A, Jinek M, Hartl M, Clausen T, Penninger J, Macheroux P, Weitzer S, Martinez J. The oxidoreductase PYROXD1 uses NAD(P)(+) as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response. Mol Cell. 2021 Apr 23. pii: S1097-2765(21)00312-9. doi:, 10.1016/j.molcel.2021.04.007. PMID:33930333 doi:http://dx.doi.org/10.1016/j.molcel.2021.04.007

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/6zk7"

@@ Line 3: / Line 3: @@
 <StructureSection load='6zk7' size='340' side='right'caption='[[6zk7]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6zk7]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZK7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZK7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6zk7]] is a 1 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=6ZK7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZK7 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</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]] 3.2&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene>, <scene name='pdbligand=MSE:SELENOMETHIONINE'>MSE</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PYROXD1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=6zk7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zk7 OCA], [https://pdbe.org/6zk7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zk7 RCSB], [https://www.ebi.ac.uk/pdbsum/6zk7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zk7 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/PYRD1_HUMAN PYRD1_HUMAN]] The disease is caused by variants affecting the gene represented in this entry.  A mutation in PYROXD1 is the cause of autosomal recessive limb-girdle muscular dystrophy. The affected individual with a homozygous recessive PYROXD1 mutation showed progressive muscle weakness with an onset at the age of 9 years. Initial symptoms included excessive falling while running, with slowly progressive weakness. Difficulty navigating stairs by the age if 18, and loss of ambulation at the age of 37 years. Neurological examination showed proximal symmetrical muscle weakness and wasting, along with calf muscle pseudohypertrophy.<ref>PMID:30345904</ref>
+[https://www.uniprot.org/uniprot/PYRD1_HUMAN PYRD1_HUMAN] The disease is caused by variants affecting the gene represented in this entry.  A mutation in PYROXD1 is the cause of autosomal recessive limb-girdle muscular dystrophy. The affected individual with a homozygous recessive PYROXD1 mutation showed progressive muscle weakness with an onset at the age of 9 years. Initial symptoms included excessive falling while running, with slowly progressive weakness. Difficulty navigating stairs by the age if 18, and loss of ambulation at the age of 37 years. Neurological examination showed proximal symmetrical muscle weakness and wasting, along with calf muscle pseudohypertrophy.<ref>PMID:30345904</ref>
 == Function ==
-[[https://www.uniprot.org/uniprot/PYRD1_HUMAN PYRD1_HUMAN]] Probable FAD-dependent oxidoreductase; involved in the cellular oxidative stress response (PubMed:27745833). Required for normal sarcomere structure and muscle fiber integrity (By similarity).[UniProtKB:Q6PBT5]<ref>PMID:27745833</ref>
+[https://www.uniprot.org/uniprot/PYRD1_HUMAN PYRD1_HUMAN] Probable FAD-dependent oxidoreductase; involved in the cellular oxidative stress response (PubMed:27745833). Required for normal sarcomere structure and muscle fiber integrity (By similarity).[UniProtKB:Q6PBT5]<ref>PMID:27745833</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 26: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Asanovic, I]]
+[[Category: Asanovic I]]
-[[Category: Clausen, T]]
+[[Category: Clausen T]]
-[[Category: Martinez, J]]
+[[Category: Martinez J]]
-[[Category: Meinhart, A]]
+[[Category: Meinhart A]]
-[[Category: Flavoprotein]]
-[[Category: Oxidoreductase]]
-[[Category: Redox regulation]]
-[[Category: Trna ligase complex]]

6zk7

From Proteopedia

Current revision

Crystal Structure of human PYROXD1/FAD complex

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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