6b1g
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Solution structure of TDP-43 N-terminal domain dimer.== | |
| + | <StructureSection load='6b1g' size='340' side='right' caption='[[6b1g]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6b1g]] is a 2 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B1G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6B1G FirstGlance]. <br> | ||
| + | </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=6b1g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b1g OCA], [http://pdbe.org/6b1g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6b1g RCSB], [http://www.ebi.ac.uk/pdbsum/6b1g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6b1g ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [[http://www.uniprot.org/uniprot/TADBP_HUMAN TADBP_HUMAN]] Defects in TARDBP are the cause of amyotrophic lateral sclerosis type 10 (ALS10) [MIM:[http://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 == | ||
| + | [[http://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 == | ||
| + | TDP-43 is an RNA-binding protein active in splicing that concentrates into membraneless ribonucleoprotein granules and forms aggregates in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Although best known for its predominantly disordered C-terminal domain which mediates ALS inclusions, TDP-43 has a globular N-terminal domain (NTD). Here, we show that TDP-43 NTD assembles into head-to-tail linear chains and that phosphomimetic substitution at S48 disrupts TDP-43 polymeric assembly, discourages liquid-liquid phase separation (LLPS) in vitro, fluidizes liquid-liquid phase separated nuclear TDP-43 reporter constructs in cells, and disrupts RNA splicing activity. Finally, we present the solution NMR structure of a head-to-tail NTD dimer comprised of two engineered variants that allow saturation of the native polymerization interface while disrupting higher-order polymerization. These data provide structural detail for the established mechanistic role of the well-folded TDP-43 NTD in splicing and link this function to LLPS. In addition, the fusion-tag solubilized, recombinant form of TDP-43 full-length protein developed here will enable future phase separation and in vitro biochemical assays on TDP-43 function and interactions that have been hampered in the past by TDP-43 aggregation. | ||
| - | + | A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing.,Wang A, Conicella AE, Schmidt HB, Martin EW, Rhoads SN, Reeb AN, Nourse A, Ramirez Montero D, Ryan VH, Rohatgi R, Shewmaker F, Naik MT, Mittag T, Ayala YM, Fawzi NL EMBO J. 2018 Feb 9. pii: embj.201797452. doi: 10.15252/embj.201797452. PMID:29438978<ref>PMID:29438978</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| + | <div class="pdbe-citations 6b1g" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
[[Category: Conicella, A]] | [[Category: Conicella, A]] | ||
| + | [[Category: Fawzi, N L]] | ||
| + | [[Category: Naik, M T]] | ||
[[Category: Wang, A]] | [[Category: Wang, A]] | ||
| - | [[Category: | + | [[Category: Amyotrophic lateral sclerosis]] |
| - | [[Category: | + | [[Category: Dimerization]] |
| + | [[Category: Protein aggregation]] | ||
| + | [[Category: Protein self-assembly]] | ||
| + | [[Category: Rna binding protein]] | ||
| + | [[Category: Structural protein]] | ||
| + | [[Category: Tdp-43]] | ||
Revision as of 06:30, 28 February 2018
Solution structure of TDP-43 N-terminal domain dimer.
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