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| | <StructureSection load='7u0z' size='340' side='right'caption='[[7u0z]], [[Resolution|resolution]] 4.20Å' scene=''> | | <StructureSection load='7u0z' size='340' side='right'caption='[[7u0z]], [[Resolution|resolution]] 4.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7u0z]] is a 3 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=7U0Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7U0Z FirstGlance]. <br> | + | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7U0Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7U0Z FirstGlance]. <br> |
| | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 4.2Å</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]] 4.2Å</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=7u0z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7u0z OCA], [https://pdbe.org/7u0z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7u0z RCSB], [https://www.ebi.ac.uk/pdbsum/7u0z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7u0z ProSAT]</span></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=7u0z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7u0z OCA], [https://pdbe.org/7u0z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7u0z RCSB], [https://www.ebi.ac.uk/pdbsum/7u0z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7u0z ProSAT]</span></td></tr> |
| | </table> | | </table> |
| - | == Disease == | + | <div style="background-color:#fffaf0;"> |
| - | [https://www.uniprot.org/uniprot/TAU_HUMAN TAU_HUMAN] Note=In Alzheimer disease, the neuronal cytoskeleton in the brain is progressively disrupted and replaced by tangles of paired helical filaments (PHF) and straight filaments, mainly composed of hyperphosphorylated forms of TAU (PHF-TAU or AD P-TAU). O-GlcNAcylation is greatly reduced in Alzheimer disease brain cerebral cortex leading to an increase in TAU/MAPT phosphorylations.<ref>PMID:19451179</ref> <ref>PMID:2484340</ref> <ref>PMID:14517953</ref> Defects in MAPT are a cause of frontotemporal dementia (FTD) [MIM:[https://omim.org/entry/600274 600274]; also called frontotemporal dementia (FTD), pallido-ponto-nigral degeneration (PPND) or historically termed Pick complex. This form of frontotemporal dementia is characterized by presenile dementia with behavioral changes, deterioration of cognitive capacities and loss of memory. In some cases, parkinsonian symptoms are prominent. Neuropathological changes include frontotemporal atrophy often associated with atrophy of the basal ganglia, substantia nigra, amygdala. In most cases, protein tau deposits are found in glial cells and/or neurons.<ref>PMID:19451179</ref> <ref>PMID:2484340</ref> <ref>PMID:14517953</ref> <ref>PMID:9629852</ref> <ref>PMID:9736786</ref> <ref>PMID:9641683</ref> <ref>PMID:9789048</ref> <ref>PMID:9973279</ref> <ref>PMID:10553987</ref> <ref>PMID:10214944</ref> <ref>PMID:10374757</ref> <ref>PMID:10489057</ref> <ref>PMID:10208578</ref> <ref>PMID:11117541</ref> <ref>PMID:10802785</ref> <ref>PMID:11071507</ref> <ref>PMID:11585254</ref> <ref>PMID:11278002</ref> <ref>PMID:12473774</ref> <ref>PMID:11921059</ref> <ref>PMID:11906000</ref> <ref>PMID:11889249</ref> <ref>PMID:12509859</ref> <ref>PMID:16240366</ref> <ref>PMID:15883319</ref> Defects in MAPT are a cause of Pick disease of the brain (PIDB) [MIM:[https://omim.org/entry/172700 172700]. It is a rare form of dementia pathologically defined by severe atrophy, neuronal loss and gliosis. It is characterized by the occurrence of tau-positive inclusions, swollen neurons (Pick cells) and argentophilic neuronal inclusions known as Pick bodies that disproportionally affect the frontal and temporal cortical regions. Clinical features include aphasia, apraxia, confusion, anomia, memory loss and personality deterioration.<ref>PMID:19451179</ref> <ref>PMID:2484340</ref> <ref>PMID:14517953</ref> <ref>PMID:10604746</ref> <ref>PMID:11117542</ref> <ref>PMID:11089577</ref> <ref>PMID:11601501</ref> <ref>PMID:11891833</ref> Note=Defects in MAPT are a cause of corticobasal degeneration (CBD). It is marked by extrapyramidal signs and apraxia and can be associated with memory loss. Neuropathologic features may overlap Alzheimer disease, progressive supranuclear palsy, and Parkinson disease.<ref>PMID:19451179</ref> <ref>PMID:2484340</ref> <ref>PMID:14517953</ref> Defects in MAPT are a cause of progressive supranuclear palsy type 1 (PSNP1) [MIM:[https://omim.org/entry/601104 601104]; also abbreviated as PSP and also known as Steele-Richardson-Olszewski syndrome. PSNP1 is characterized by akinetic-rigid syndrome, supranuclear gaze palsy, pyramidal tract dysfunction, pseudobulbar signs and cognitive capacities deterioration. Neurofibrillary tangles and gliosis but no amyloid plaques are found in diseased brains. Most cases appear to be sporadic, with a significant association with a common haplotype including the MAPT gene and the flanking regions. Familial cases show an autosomal dominant pattern of transmission with incomplete penetrance; genetic analysis of a few cases showed the occurrence of tau mutations, including a deletion of Asn-613.<ref>PMID:19451179</ref> <ref>PMID:2484340</ref> <ref>PMID:14517953</ref> <ref>PMID:10534245</ref> <ref>PMID:11220749</ref> <ref>PMID:12325083</ref> <ref>PMID:14991829</ref> <ref>PMID:14991828</ref> <ref>PMID:16157753</ref> Defects in MAPT are a cause of Parkinson-dementia syndrome (PARDE) [MIM:[https://omim.org/entry/260540 260540]. A syndrome characterized by parkinsonism tremor, rigidity, dementia, ophthalmoparesis and pyramidal signs. Neurofibrillary degeneration occurs in the hippocampus, basal ganglia and brainstem nuclei.<ref>PMID:19451179</ref> <ref>PMID:2484340</ref> <ref>PMID:14517953</ref>
| + | == Publication Abstract from PubMed == |
| - | == Function ==
| + | Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or alpha-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 A from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration. |
| - | [https://www.uniprot.org/uniprot/TAU_HUMAN TAU_HUMAN] Promotes microtubule assembly and stability, and might be involved in the establishment and maintenance of neuronal polarity. The C-terminus binds axonal microtubules while the N-terminus binds neural plasma membrane components, suggesting that tau functions as a linker protein between both. Axonal polarity is predetermined by TAU/MAPT localization (in the neuronal cell) in the domain of the cell body defined by the centrosome. The short isoforms allow plasticity of the cytoskeleton whereas the longer isoforms may preferentially play a role in its stabilization.<ref>PMID:21985311</ref>
| + | |
| | + | Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.,Chang A, Xiang X, Wang J, Lee C, Arakhamia T, Simjanoska M, Wang C, Carlomagno Y, Zhang G, Dhingra S, Thierry M, Perneel J, Heeman B, Forgrave LM, DeTure M, DeMarco ML, Cook CN, Rademakers R, Dickson DW, Petrucelli L, Stowell MHB, Mackenzie IRA, Fitzpatrick AWP Cell. 2022 Mar 1. pii: S0092-8674(22)00259-8. doi: 10.1016/j.cell.2022.02.026. PMID:35247328<ref>PMID:35247328</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 7u0z" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Homo sapiens]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| | [[Category: Arakhamia T]] | | [[Category: Arakhamia T]] |
| Structural highlights
Publication Abstract from PubMed
Misfolding and aggregation of disease-specific proteins, resulting in the formation of filamentous cellular inclusions, is a hallmark of neurodegenerative disease with characteristic filament structures, or conformers, defining each proteinopathy. Here we show that a previously unsolved amyloid fibril composed of a 135 amino acid C-terminal fragment of TMEM106B is a common finding in distinct human neurodegenerative diseases, including cases characterized by abnormal aggregation of TDP-43, tau, or alpha-synuclein protein. A combination of cryoelectron microscopy and mass spectrometry was used to solve the structures of TMEM106B fibrils at a resolution of 2.7 A from postmortem human brain tissue afflicted with frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP, n = 8), progressive supranuclear palsy (PSP, n = 2), or dementia with Lewy bodies (DLB, n = 1). The commonality of abundant amyloid fibrils composed of TMEM106B, a lysosomal/endosomal protein, to a broad range of debilitating human disorders indicates a shared fibrillization pathway that may initiate or accelerate neurodegeneration.
Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.,Chang A, Xiang X, Wang J, Lee C, Arakhamia T, Simjanoska M, Wang C, Carlomagno Y, Zhang G, Dhingra S, Thierry M, Perneel J, Heeman B, Forgrave LM, DeTure M, DeMarco ML, Cook CN, Rademakers R, Dickson DW, Petrucelli L, Stowell MHB, Mackenzie IRA, Fitzpatrick AWP Cell. 2022 Mar 1. pii: S0092-8674(22)00259-8. doi: 10.1016/j.cell.2022.02.026. PMID:35247328[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chang A, Xiang X, Wang J, Lee C, Arakhamia T, Simjanoska M, Wang C, Carlomagno Y, Zhang G, Dhingra S, Thierry M, Perneel J, Heeman B, Forgrave LM, DeTure M, DeMarco ML, Cook CN, Rademakers R, Dickson DW, Petrucelli L, Stowell MHB, Mackenzie IRA, Fitzpatrick AWP. Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases. Cell. 2022 Mar 1. pii: S0092-8674(22)00259-8. doi: 10.1016/j.cell.2022.02.026. PMID:35247328 doi:http://dx.doi.org/10.1016/j.cell.2022.02.026
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