7saq

From Proteopedia

(Difference between revisions)

Revision as of 13:07, 4 May 2022

Cryo-EM structure of TMEM106B fibrils extracted from a FTLD-TDP patient, polymorph 1

Structural highlights

7saq is a 5 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[T106B_HUMAN] Progressive non-fluent aphasia;Semantic dementia;Behavioral variant of frontotemporal dementia. The gene represented in this entry acts as a disease modifier. Risk alleles confer genetic susceptibility by increasing gene expression (PubMed:20154673, PubMed:21178100). Increased expression may be the result of down-regulation of microRNA miR-132 and miR-212, that repress TMEM106B expression (PubMed:22895706). Thr-185 is a risk allele associated with lower GRN protein levels and early age at onset in GRN UP-FTD mutation carriers: it presents slower protein degradation that leads to higher steady-state TMEM106B levels, leading to alterations in the intracellular versus extracellular partitioning of GRN (PubMed:23742080).^[1] ^[2] ^[3] ^[4] The gene represented in this entry acts as a disease modifier. The disease may be caused by variants affecting the gene represented in this entry.

Function

[T106B_HUMAN] Involved in dendrite morphogenesis and maintenance by regulating lysosomal trafficking via its interaction with MAP6. May act by inhibiting retrograde transport of lysosomes along dendrites. Required for dendrite branching.^[5] ^[6]

Publication Abstract from PubMed

Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative condition, following only Alzheimer's and Parkinson's diseases(1). FTLD typically presents in 45-64-year-olds with behavioral changes or progressive decline of language skills(2). The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions detected by TAR DNA-binding protein (TDP-43) immunoreactivity(3). Here, we extracted amyloid fibrils from brains of four patients, representing four out of five FTLD-TDP subclasses and determined their near-atomic resolution structures by cryogenic electron-microscopy (cryo-EM). Unexpectedly, all amyloid fibrils examined are composed of a 135-residue C-terminal fragment of transmembrane protein 106B (TMEM106B), a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP(4). In addition to TMEM106B fibrils, abundant non-fibrillar aggregated TDP-43 is present, as revealed by immunogold labeling. Our observations confirm that FTLD-TDP is an amyloid-involved disease and suggest that amyloid involvement in FTLD-TDP is of protein TMEM106B, rather than of TDP-43.

Amyloid fibrils in disease FTLD-TDP are composed of TMEM106B not TDP-43.,Jiang YX, Cao Q, Sawaya MR, Abskharon R, Ge P, DeTure M, Dickson DW, Fu JY, Ogorzalek Loo RR, Loo JA, Eisenberg DS Nature. 2022 Mar 28. pii: 10.1038/s41586-022-04670-9. doi:, 10.1038/s41586-022-04670-9. PMID:35344984^[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR, Dickson DW, Rademakers R, Boeve BF, Grossman M, Arnold SE, Mann DM, Pickering-Brown SM, Seelaar H, Heutink P, van Swieten JC, Murrell JR, Ghetti B, Spina S, Grafman J, Hodges J, Spillantini MG, Gilman S, Lieberman AP, Kaye JA, Woltjer RL, Bigio EH, Mesulam M, Al-Sarraj S, Troakes C, Rosenberg RN, White CL 3rd, Ferrer I, Llado A, Neumann M, Kretzschmar HA, Hulette CM, Welsh-Bohmer KA, Miller BL, Alzualde A, Lopez de Munain A, McKee AC, Gearing M, Levey AI, Lah JJ, Hardy J, Rohrer JD, Lashley T, Mackenzie IR, Feldman HH, Hamilton RL, Dekosky ST, van der Zee J, Kumar-Singh S, Van Broeckhoven C, Mayeux R, Vonsattel JP, Troncoso JC, Kril JJ, Kwok JB, Halliday GM, Bird TD, Ince PG, Shaw PJ, Cairns NJ, Morris JC, McLean CA, DeCarli C, Ellis WG, Freeman SH, Frosch MP, Growdon JH, Perl DP, Sano M, Bennett DA, Schneider JA, Beach TG, Reiman EM, Woodruff BK, Cummings J, Vinters HV, Miller CA, Chui HC, Alafuzoff I, Hartikainen P, Seilhean D, Galasko D, Masliah E, Cotman CW, Tunon MT, Martinez MC, Munoz DG, Carroll SL, Marson D, Riederer PF, Bogdanovic N, Schellenberg GD, Hakonarson H, Trojanowski JQ, Lee VM. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet. 2010 Mar;42(3):234-9. doi: 10.1038/ng.536. Epub 2010 Feb 14. PMID:20154673 doi:http://dx.doi.org/10.1038/ng.536
↑ Finch N, Carrasquillo MM, Baker M, Rutherford NJ, Coppola G, Dejesus-Hernandez M, Crook R, Hunter T, Ghidoni R, Benussi L, Crook J, Finger E, Hantanpaa KJ, Karydas AM, Sengdy P, Gonzalez J, Seeley WW, Johnson N, Beach TG, Mesulam M, Forloni G, Kertesz A, Knopman DS, Uitti R, White CL 3rd, Caselli R, Lippa C, Bigio EH, Wszolek ZK, Binetti G, Mackenzie IR, Miller BL, Boeve BF, Younkin SG, Dickson DW, Petersen RC, Graff-Radford NR, Geschwind DH, Rademakers R. TMEM106B regulates progranulin levels and the penetrance of FTLD in GRN mutation carriers. Neurology. 2011 Feb 1;76(5):467-74. doi: 10.1212/WNL.0b013e31820a0e3b. Epub 2010 , Dec 22. PMID:21178100 doi:http://dx.doi.org/10.1212/WNL.0b013e31820a0e3b
↑ Chen-Plotkin AS, Unger TL, Gallagher MD, Bill E, Kwong LK, Volpicelli-Daley L, Busch JI, Akle S, Grossman M, Van Deerlin V, Trojanowski JQ, Lee VM. TMEM106B, the risk gene for frontotemporal dementia, is regulated by the microRNA-132/212 cluster and affects progranulin pathways. J Neurosci. 2012 Aug 15;32(33):11213-27. doi: 10.1523/JNEUROSCI.0521-12.2012. PMID:22895706 doi:http://dx.doi.org/10.1523/JNEUROSCI.0521-12.2012
↑ Nicholson AM, Finch NA, Wojtas A, Baker MC, Perkerson RB 3rd, Castanedes-Casey M, Rousseau L, Benussi L, Binetti G, Ghidoni R, Hsiung GY, Mackenzie IR, Finger E, Boeve BF, Ertekin-Taner N, Graff-Radford NR, Dickson DW, Rademakers R. TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia. J Neurochem. 2013 Sep;126(6):781-91. doi: 10.1111/jnc.12329. Epub 2013 Jul 1. PMID:23742080 doi:http://dx.doi.org/10.1111/jnc.12329
↑ Brady OA, Zheng Y, Murphy K, Huang M, Hu F. The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum Mol Genet. 2013 Feb 15;22(4):685-95. doi: 10.1093/hmg/dds475. Epub 2012 Nov, 6. PMID:23136129 doi:http://dx.doi.org/10.1093/hmg/dds475
↑ Schwenk BM, Lang CM, Hogl S, Tahirovic S, Orozco D, Rentzsch K, Lichtenthaler SF, Hoogenraad CC, Capell A, Haass C, Edbauer D. The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. EMBO J. 2014 Mar 3;33(5):450-67. doi: 10.1002/embj.201385857. Epub 2013 Dec 19. PMID:24357581 doi:http://dx.doi.org/10.1002/embj.201385857
↑ Jiang YX, Cao Q, Sawaya MR, Abskharon R, Ge P, DeTure M, Dickson DW, Fu JY, Ogorzalek Loo RR, Loo JA, Eisenberg DS. Amyloid fibrils in disease FTLD-TDP are composed of TMEM106B not TDP-43. Nature. 2022 Mar 28. pii: 10.1038/s41586-022-04670-9. doi:, 10.1038/s41586-022-04670-9. PMID:35344984 doi:http://dx.doi.org/10.1038/s41586-022-04670-9

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7saq"

@@ Line 1: / Line 1: @@
 ==Cryo-EM structure of TMEM106B fibrils extracted from a FTLD-TDP patient, polymorph 1==
-<StructureSection load='7saq' size='340' side='right'caption='[[7saq]]' scene=''>
+<StructureSection load='7saq' size='340' side='right'caption='[[7saq]], [[Resolution|resolution]] 2.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7SAQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SAQ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7saq]] is a 5 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=7SAQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SAQ 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=7saq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7saq OCA], [https://pdbe.org/7saq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7saq RCSB], [https://www.ebi.ac.uk/pdbsum/7saq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7saq ProSAT]</span></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=7saq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7saq OCA], [https://pdbe.org/7saq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7saq RCSB], [https://www.ebi.ac.uk/pdbsum/7saq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7saq ProSAT]</span></td></tr>
 </table>
+== Disease ==
+[[https://www.uniprot.org/uniprot/T106B_HUMAN T106B_HUMAN]] Progressive non-fluent aphasia;Semantic dementia;Behavioral variant of frontotemporal dementia. The gene represented in this entry acts as a disease modifier. Risk alleles confer genetic susceptibility by increasing gene expression (PubMed:20154673, PubMed:21178100). Increased expression may be the result of down-regulation of microRNA miR-132 and miR-212, that repress TMEM106B expression (PubMed:22895706). Thr-185 is a risk allele associated with lower GRN protein levels and early age at onset in GRN UP-FTD mutation carriers: it presents slower protein degradation that leads to higher steady-state TMEM106B levels, leading to alterations in the intracellular versus extracellular partitioning of GRN (PubMed:23742080).<ref>PMID:20154673</ref> <ref>PMID:21178100</ref> <ref>PMID:22895706</ref> <ref>PMID:23742080</ref>   The gene represented in this entry acts as a disease modifier.  The disease may be caused by variants affecting the gene represented in this entry.
+== Function ==
+[[https://www.uniprot.org/uniprot/T106B_HUMAN T106B_HUMAN]] Involved in dendrite morphogenesis and maintenance by regulating lysosomal trafficking via its interaction with MAP6. May act by inhibiting retrograde transport of lysosomes along dendrites. Required for dendrite branching.<ref>PMID:23136129</ref> <ref>PMID:24357581</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative condition, following only Alzheimer's and Parkinson's diseases(1). FTLD typically presents in 45-64-year-olds with behavioral changes or progressive decline of language skills(2). The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions detected by TAR DNA-binding protein (TDP-43) immunoreactivity(3). Here, we extracted amyloid fibrils from brains of four patients, representing four out of five FTLD-TDP subclasses and determined their near-atomic resolution structures by cryogenic electron-microscopy (cryo-EM). Unexpectedly, all amyloid fibrils examined are composed of a 135-residue C-terminal fragment of transmembrane protein 106B (TMEM106B), a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP(4). In addition to TMEM106B fibrils, abundant non-fibrillar aggregated TDP-43 is present, as revealed by immunogold labeling. Our observations confirm that FTLD-TDP is an amyloid-involved disease and suggest that amyloid involvement in FTLD-TDP is of protein TMEM106B, rather than of TDP-43.
+Amyloid fibrils in disease FTLD-TDP are composed of TMEM106B not TDP-43.,Jiang YX, Cao Q, Sawaya MR, Abskharon R, Ge P, DeTure M, Dickson DW, Fu JY, Ogorzalek Loo RR, Loo JA, Eisenberg DS Nature. 2022 Mar 28. pii: 10.1038/s41586-022-04670-9. doi:, 10.1038/s41586-022-04670-9. PMID:35344984<ref>PMID:35344984</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 7saq" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
 __TOC__
 </StructureSection>
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Cao Q]]
+[[Category: Cao, Q]]
-[[Category: Eisenberg DS]]
+[[Category: Eisenberg, D S]]
-[[Category: Jiang Y]]
+[[Category: Jiang, Y]]
-[[Category: Sawaya MR]]
+[[Category: Sawaya, M R]]
+[[Category: Amyloid]]
+[[Category: Ftld-tdp]]
+[[Category: Protein fibril]]
+[[Category: Tmem106b]]

7saq

From Proteopedia

Revision as of 13:07, 4 May 2022

Cryo-EM structure of TMEM106B fibrils extracted from a FTLD-TDP patient, polymorph 1

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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