View source for 7sas


==Cryo-EM structure of TMEM106B fibrils extracted from a FTLD-TDP patient, polymorph 3==
<StructureSection load='7sas' size='340' side='right'caption='[[7sas]], [[Resolution|resolution]] 3.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7sas]] is a 10 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=7SAS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SAS FirstGlance]. <br>
</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=7sas FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7sas OCA], [https://pdbe.org/7sas PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7sas RCSB], [https://www.ebi.ac.uk/pdbsum/7sas PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7sas 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>  
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== 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>
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<div class="pdbe-citations 7sas" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cao, Q]]
[[Category: Eisenberg, D S]]
[[Category: Jiang, Y]]
[[Category: Sawaya, M R]]
[[Category: Amyloid]]
[[Category: Ftld-tdp]]
[[Category: Protein fibril]]
[[Category: Tmem106b]]