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| <StructureSection load='7py2' size='340' side='right'caption='[[7py2]], [[Resolution|resolution]] 2.60Å' scene=''> | | <StructureSection load='7py2' size='340' side='right'caption='[[7py2]], [[Resolution|resolution]] 2.60Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[7py2]] 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=7PY2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PY2 FirstGlance]. <br> | | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7PY2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7PY2 FirstGlance]. <br> |
| </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=7py2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7py2 OCA], [https://pdbe.org/7py2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7py2 RCSB], [https://www.ebi.ac.uk/pdbsum/7py2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7py2 ProSAT]</span></td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.6Å</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=7py2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7py2 OCA], [https://pdbe.org/7py2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7py2 RCSB], [https://www.ebi.ac.uk/pdbsum/7py2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7py2 ProSAT]</span></td></tr> |
| </table> | | </table> |
| == Disease ==
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| [[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>
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| == Function ==
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| [[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>
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| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| The abnormal aggregation of TAR DNA-binding protein 43 kDa (TDP-43) in neurons and glia is the defining pathological hallmark of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) and multiple forms of frontotemporal lobar degeneration (FTLD)(1,2). It is also common in other diseases, including Alzheimer's and Parkinson's. No disease-modifying therapies exist for these conditions and early diagnosis is not possible. The structures of pathological TDP-43 aggregates are unknown. Here we used cryo-electron microscopy to determine the structures of aggregated TDP-43 in the frontal and motor cortices of an individual who had ALS with FTLD and from the frontal cortex of a second individual with the same diagnosis. An identical amyloid-like filament structure comprising a single protofilament was found in both brain regions and individuals. The ordered filament core spans residues 282-360 in the TDP-43 low-complexity domain and adopts a previously undescribed double-spiral-shaped fold, which shows no similarity to those of TDP-43 filaments formed in vitro(3,4). An abundance of glycine and neutral polar residues facilitates numerous turns and restricts beta-strand length, which results in an absence of beta-sheet stacking that is associated with cross-beta amyloid structure. An uneven distribution of residues gives rise to structurally and chemically distinct surfaces that face external densities and suggest possible ligand-binding sites. This work enhances our understanding of the molecular pathogenesis of ALS and FTLD and informs the development of diagnostic and therapeutic agents that target aggregated TDP-43.
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| Structure of pathological TDP-43 filaments from ALS with FTLD.,Arseni D, Hasegawa M, Murzin AG, Kametani F, Arai M, Yoshida M, Ryskeldi-Falcon B Nature. 2021 Dec 8. pii: 10.1038/s41586-021-04199-3. doi:, 10.1038/s41586-021-04199-3. PMID:34880495<ref>PMID:34880495</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 7py2" style="background-color:#fffaf0;"></div>
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| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Homo sapiens]]
| |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Arai, M]] | | [[Category: Arai M]] |
| [[Category: Arseni, D]] | | [[Category: Arseni D]] |
| [[Category: Falcon, B]] | | [[Category: Falcon B]] |
| [[Category: Hasegawa, H]] | | [[Category: Hasegawa H]] |
| [[Category: Kametani, F]] | | [[Category: Kametani F]] |
| [[Category: Murzin, A G]] | | [[Category: Murzin AG]] |
| [[Category: Yoshida, M]] | | [[Category: Yoshida M]] |
| [[Category: Al]]
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| [[Category: Amyloid]]
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| [[Category: Amyotrophic lateral sclerosis]]
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| [[Category: Fibril]]
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| [[Category: Filament]]
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| [[Category: Frontotemporal dementia]]
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| [[Category: Frontotemporal lobar degeneration]]
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| [[Category: Ftd]]
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| [[Category: Ftld]]
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| [[Category: Neurodegeneration]]
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| [[Category: Neurodegenerative]]
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| [[Category: Protein fibril]]
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| [[Category: Tdp-43]]
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