6n3c

From Proteopedia

(Difference between revisions)

Current revision

SegB, conformation of TDP-43 low complexity domain segment A

6n3c, resolution 3.30Å

Structural highlights

6n3c is a 20 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:	Electron Microscopy, Resolution 3.3Å
Experimental data:	Check to display Experimental Data
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TADBP_HUMAN Defects in TARDBP are the cause of amyotrophic lateral sclerosis type 10 (ALS10) [MIM: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.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13]

Function

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.^[14] ^[15]

References

↑ Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, Armakola M, Geser F, Greene R, Lu MM, Padmanabhan A, Clay-Falcone D, McCluskey L, Elman L, Juhr D, Gruber PJ, Rub U, Auburger G, Trojanowski JQ, Lee VM, Van Deerlin VM, Bonini NM, Gitler AD. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010 Aug 26;466(7310):1069-75. doi: 10.1038/nature09320. PMID:20740007 doi:10.1038/nature09320
↑ Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, White CL 3rd, Bigio EH, Caselli R, Baker M, Al-Lozi MT, Morris JC, Pestronk A, Rademakers R, Goate AM, Cairns NJ. TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol. 2008 Apr;63(4):535-8. doi: 10.1002/ana.21344. PMID:18288693 doi:10.1002/ana.21344
↑ Yokoseki A, Shiga A, Tan CF, Tagawa A, Kaneko H, Koyama A, Eguchi H, Tsujino A, Ikeuchi T, Kakita A, Okamoto K, Nishizawa M, Takahashi H, Onodera O. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol. 2008 Apr;63(4):538-42. doi: 10.1002/ana.21392. PMID:18438952 doi:10.1002/ana.21392
↑ Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, Clay D, Wood EM, Chen-Plotkin AS, Martinez-Lage M, Steinbart E, McCluskey L, Grossman M, Neumann M, Wu IL, Yang WS, Kalb R, Galasko DR, Montine TJ, Trojanowski JQ, Lee VM, Schellenberg GD, Yu CE. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008 May;7(5):409-16. doi: 10.1016/S1474-4422(08)70071-1. Epub, 2008 Apr 7. PMID:18396105 doi:10.1016/S1474-4422(08)70071-1
↑ Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F, Pradat PF, Camu W, Meininger V, Dupre N, Rouleau GA. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008 May;40(5):572-4. doi: 10.1038/ng.132. Epub 2008 Mar 30. PMID:18372902 doi:10.1038/ng.132
↑ Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008 Mar 21;319(5870):1668-72. doi: 10.1126/science.1154584. Epub 2008, Feb 28. PMID:18309045 doi:10.1126/science.1154584
↑ Benajiba L, Le Ber I, Camuzat A, Lacoste M, Thomas-Anterion C, Couratier P, Legallic S, Salachas F, Hannequin D, Decousus M, Lacomblez L, Guedj E, Golfier V, Camu W, Dubois B, Campion D, Meininger V, Brice A. TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration. Ann Neurol. 2009 Apr;65(4):470-3. doi: 10.1002/ana.21612. PMID:19350673 doi:10.1002/ana.21612
↑ Corrado L, Ratti A, Gellera C, Buratti E, Castellotti B, Carlomagno Y, Ticozzi N, Mazzini L, Testa L, Taroni F, Baralle FE, Silani V, D'Alfonso S. High frequency of TARDBP gene mutations in Italian patients with amyotrophic lateral sclerosis. Hum Mutat. 2009 Apr;30(4):688-94. doi: 10.1002/humu.20950. PMID:19224587 doi:10.1002/humu.20950
↑ Borroni B, Bonvicini C, Alberici A, Buratti E, Agosti C, Archetti S, Papetti A, Stuani C, Di Luca M, Gennarelli M, Padovani A. Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease. Hum Mutat. 2009 Nov;30(11):E974-83. doi: 10.1002/humu.21100. PMID:19655382 doi:10.1002/humu.21100
↑ Luquin N, Yu B, Saunderson RB, Trent RJ, Pamphlett R. Genetic variants in the promoter of TARDBP in sporadic amyotrophic lateral sclerosis. Neuromuscul Disord. 2009 Oct;19(10):696-700. doi: 10.1016/j.nmd.2009.07.005. Epub, 2009 Aug 19. PMID:19695877 doi:10.1016/j.nmd.2009.07.005
↑ Chio A, Borghero G, Pugliatti M, Ticca A, Calvo A, Moglia C, Mutani R, Brunetti M, Ossola I, Marrosu MG, Murru MR, Floris G, Cannas A, Parish LD, Cossu P, Abramzon Y, Johnson JO, Nalls MA, Arepalli S, Chong S, Hernandez DG, Traynor BJ, Restagno G. Large proportion of amyotrophic lateral sclerosis cases in Sardinia due to a single founder mutation of the TARDBP gene. Arch Neurol. 2011 May;68(5):594-8. doi: 10.1001/archneurol.2010.352. Epub 2011, Jan 10. PMID:21220647 doi:10.1001/archneurol.2010.352
↑ Orru S, Manolakos E, Orru N, Kokotas H, Mascia V, Carcassi C, Petersen MB. High frequency of the TARDBP p.Ala382Thr mutation in Sardinian patients with amyotrophic lateral sclerosis. Clin Genet. 2012 Feb;81(2):172-8. doi: 10.1111/j.1399-0004.2011.01668.x. Epub, 2011 Apr 18. PMID:21418058 doi:10.1111/j.1399-0004.2011.01668.x
↑ Chiang HH, Andersen PM, Tysnes OB, Gredal O, Christensen PB, Graff C. Novel TARDBP mutations in Nordic ALS patients. J Hum Genet. 2012 May;57(5):316-9. doi: 10.1038/jhg.2012.24. Epub 2012 Mar 29. PMID:22456481 doi:10.1038/jhg.2012.24
↑ Strong MJ, Volkening K, Hammond R, Yang W, Strong W, Leystra-Lantz C, Shoesmith C. TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol Cell Neurosci. 2007 Jun;35(2):320-7. Epub 2007 Mar 20. PMID:17481916 doi:10.1016/j.mcn.2007.03.007
↑ Buratti E, Dork T, Zuccato E, Pagani F, Romano M, Baralle FE. Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J. 2001 Apr 2;20(7):1774-84. PMID:11285240 doi:10.1093/emboj/20.7.1774

1 Structural highlights
2 Disease
3 Function
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6n3c"

@@ Line 3: / Line 3: @@
 <SX load='6n3c' size='340' side='right' viewer='molstar' caption='[[6n3c]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6n3c]] is a 20 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6N3C OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6N3C FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6n3c]] is a 20 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=6N3C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6N3C FirstGlance]. <br>
-</td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6n3a|6n3a]], [[6n37|6n37]], [[6n3b|6n3b]]</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]] 3.3&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">TARDBP, TDP43 ([http://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=6n3c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n3c OCA], [https://pdbe.org/6n3c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6n3c RCSB], [https://www.ebi.ac.uk/pdbsum/6n3c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6n3c ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6n3c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6n3c OCA], [http://pdbe.org/6n3c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6n3c RCSB], [http://www.ebi.ac.uk/pdbsum/6n3c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6n3c 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>
+[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 ==
-[[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>
+[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 DNA and RNA processing protein TDP-43 undergoes both functional and pathogenic aggregation. Functional TDP-43 aggregates form reversible, transient species such as nuclear bodies, stress granules, and myo-granules. Pathogenic, irreversible TDP-43 aggregates form in amyotrophic lateral sclerosis and other neurodegenerative conditions. Here we find the features of TDP-43 fibrils that confer both reversibility and irreversibility by determining structures of two segments reported to be the pathogenic cores of human TDP-43 aggregation: SegA (residues 311-360), which forms three polymorphs, all with dagger-shaped folds; and SegB A315E (residues 286-331 containing the amyotrophic lateral sclerosis hereditary mutation A315E), which forms R-shaped folds. Energetic analysis suggests that the dagger-shaped polymorphs represent irreversible fibril structures, whereas the SegB polymorph may participate in both reversible and irreversible fibrils. Our structures reveal the polymorphic nature of TDP-43 and suggest how the A315E mutation converts the R-shaped polymorph to an irreversible form that enhances pathology.
-Cryo-EM structures of four polymorphic TDP-43 amyloid cores.,Cao Q, Boyer DR, Sawaya MR, Ge P, Eisenberg DS Nat Struct Mol Biol. 2019 Jul;26(7):619-627. doi: 10.1038/s41594-019-0248-4. Epub, 2019 Jun 24. PMID:31235914<ref>PMID:31235914</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 6n3c" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </SX>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Boyer, D R]]
+[[Category: Boyer DR]]
-[[Category: Cao, Q]]
+[[Category: Cao Q]]
-[[Category: Eisenberg, D S]]
+[[Category: Eisenberg DS]]
-[[Category: Sawaya, M R]]
+[[Category: Sawaya MR]]
-[[Category: Al]]
-[[Category: Amyloid]]
-[[Category: Dna binding protein]]
-[[Category: Ftld-tdp]]
-[[Category: Protein fibril]]
-[[Category: Tdp43]]

6n3c

From Proteopedia

Current revision

SegB, conformation of TDP-43 low complexity domain segment A

Structural highlights

Disease

Function

References

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