5x4f
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==Solution Structure of the N-terminal Domain of TDP-43== | ==Solution Structure of the N-terminal Domain of TDP-43== | ||
| - | <StructureSection load='5x4f' size='340' side='right' caption='[[5x4f | + | <StructureSection load='5x4f' size='340' side='right'caption='[[5x4f]]' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[5x4f]] is a 1 chain structure. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5X4F OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[5x4f]] 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=5X4F OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5X4F FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </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=5x4f FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5x4f OCA], [https://pdbe.org/5x4f PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5x4f RCSB], [https://www.ebi.ac.uk/pdbsum/5x4f PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5x4f ProSAT]</span></td></tr> |
</table> | </table> | ||
== Disease == | == 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 == | == 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 == | ||
| + | TDP-43 is a nuclear factor that functions in promoting pre-mRNA splicing. Deletion of the N-terminal domain (NTD) and nuclear localization signal (NLS) (i.e., TDP-35) results in mislocalization to cytoplasm and formation of inclusions. However, how the NTD functions in TDP-43 activity and proteinopathy remains largely unknown. Here, we studied the structure and function of the NTD in inclusion formation and pre-mRNA splicing of TDP-43 by using biochemical and biophysical approaches. We found that TDP-43 NTD forms a homodimer in solution in a concentration-dependent manner, and formation of intermolecular disulfide results in further tetramerization. Based on the NMR structure of TDP-43 NTD, the dimerization interface centered on Leu71 and Val72 around the beta7-strand was defined by mutagenesis and size-exclusion chromatography. Cell experiments revealed that the N-terminal dimerization plays roles in protecting TDP-43 against formation of cytoplasmic inclusions and enhancing pre-mRNA splicing activity of TDP-43 in nucleus. This study may provide mechanistic insights into the physiological function of TDP-43 and its related proteinopathies. | ||
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| + | The N-terminal dimerization is required for TDP-43 splicing activity.,Jiang LL, Xue W, Hong JY, Zhang JT, Li MJ, Yu SN, He JH, Hu HY Sci Rep. 2017 Jul 21;7(1):6196. doi: 10.1038/s41598-017-06263-3. PMID:28733604<ref>PMID:28733604</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5x4f" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Hu H-Y]] |
| - | [[Category: | + | [[Category: Jiang L-L]] |
| - | [[Category: | + | [[Category: Xue W]] |
Current revision
Solution Structure of the N-terminal Domain of TDP-43
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