8a6i
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Structure of the low complexity domain of TDP-43 (fragment 309-350) with methionine sulfoxide modifications== | |
| + | <StructureSection load='8a6i' size='340' side='right'caption='[[8a6i]]' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8a6i]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8A6I OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8A6I FirstGlance]. <br> | ||
| + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR, 20 models</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MHO:S-OXYMETHIONINE'>MHO</scene></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=8a6i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8a6i OCA], [https://pdbe.org/8a6i PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8a6i RCSB], [https://www.ebi.ac.uk/pdbsum/8a6i PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8a6i ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/TADBP_HUMAN TADBP_HUMAN] Defects in TARDBP are the cause of amyotrophic lateral sclerosis type 10 (ALS10) [MIM:[https://omim.org/entry/612069 612069]. ALS is a neurodegenerative disorder affecting upper and lower motor neurons and resulting in fatal paralysis. Sensory abnormalities are absent. Death usually occurs within 2 to 5 years. The etiology of ALS is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases.<ref>PMID:20740007</ref> <ref>PMID:18288693</ref> <ref>PMID:18438952</ref> <ref>PMID:18396105</ref> <ref>PMID:18372902</ref> <ref>PMID:18309045</ref> <ref>PMID:19350673</ref> <ref>PMID:19224587</ref> <ref>PMID:19655382</ref> <ref>PMID:19695877</ref> <ref>PMID:21220647</ref> <ref>PMID:21418058</ref> <ref>PMID:22456481</ref> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/TADBP_HUMAN TADBP_HUMAN] DNA and RNA-binding protein which regulates transcription and splicing. Involved in the regulation of CFTR splicing. It promotes CFTR exon 9 skipping by binding to the UG repeated motifs in the polymorphic region near the 3'-splice site of this exon. The resulting aberrant splicing is associated with pathological features typical of cystic fibrosis. May also be involved in microRNA biogenesis, apoptosis and cell division. Can repress HIV-1 transcription by binding to the HIV-1 long terminal repeat. Stabilizes the low molecular weight neurofilament (NFL) mRNA through a direct interaction with the 3' UTR.<ref>PMID:17481916</ref> <ref>PMID:11285240</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The RNA binding protein TDP-43 forms cytoplasmic inclusions via its C-terminal prion-like domain in several neurodegenerative diseases. Aberrant TDP-43 aggregation arises upon phase de-mixing and transitions from liquid to solid states, following still unknown structural conversions which are primed by oxidative stress and chaperone inhibition. Despite the well-established protective roles for molecular chaperones against protein aggregation pathologies, knowledge on the determinants of chaperone recognition in disease-related prions is scarce. Here we show that chaperones and co-chaperones primarily recognize the structured elements in TDP-43 s prion-like domain. Significantly, while HSP70 and HSP90 chaperones promote TDP-43 phase separation, co-chaperones from the three classes of the large human HSP40 family (namely DNAJA2, DNAJB1, DNAJB4 and DNAJC7) show strikingly different effects on TDP-43 de-mixing. Dismantling of the second helical element in TDP-43 prion-like domain by methionine sulfoxidation impacts phase separation and amyloid formation, abrogates chaperone recognition and alters phosphorylation by casein kinase-1delta. Our results show that metamorphism in the post-translationally modified TDP-43 prion-like domain encodes determinants that command mechanisms with major relevance in disease. | ||
| - | + | Metamorphism in TDP-43 prion-like domain determines chaperone recognition.,Carrasco J, Anton R, Valbuena A, Pantoja-Uceda D, Mukhi M, Hervas R, Laurents DV, Gasset M, Oroz J Nat Commun. 2023 Jan 28;14(1):466. doi: 10.1038/s41467-023-36023-z. PMID:36709343<ref>PMID:36709343</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8a6i" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Anton R]] | ||
| + | [[Category: Carrasco J]] | ||
| + | [[Category: Laurents DV]] | ||
| + | [[Category: Oroz J]] | ||
| + | [[Category: Pantoja-Uceda D]] | ||
Current revision
Structure of the low complexity domain of TDP-43 (fragment 309-350) with methionine sulfoxide modifications
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