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| <StructureSection load='7nrx' size='340' side='right'caption='[[7nrx]], [[Resolution|resolution]] 3.55Å' scene=''> | | <StructureSection load='7nrx' size='340' side='right'caption='[[7nrx]], [[Resolution|resolution]] 3.55Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[7nrx]] 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=7NRX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NRX FirstGlance]. <br> | | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7NRX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NRX 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=7nrx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nrx OCA], [https://pdbe.org/7nrx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nrx RCSB], [https://www.ebi.ac.uk/pdbsum/7nrx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nrx ProSAT]</span></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]] 3.55Å</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=7nrx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7nrx OCA], [https://pdbe.org/7nrx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7nrx RCSB], [https://www.ebi.ac.uk/pdbsum/7nrx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7nrx ProSAT]</span></td></tr> |
| </table> | | </table> |
| == Disease ==
| |
| [[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>
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| == Function ==
| |
| [[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>
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| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| Tau and Abeta assemblies of Alzheimer's disease (AD) can be visualized in living subjects using positron emission tomography (PET). Tau assemblies comprise paired helical and straight filaments (PHFs and SFs). APN-1607 (PM-PBB3) is a recently described PET ligand for AD and other tau proteinopathies. Since it is not known where in the tau folds PET ligands bind, we used electron cryo-microscopy (cryo-EM) to determine the binding sites of APN-1607 in the Alzheimer fold. We identified two major sites in the beta-helix of PHFs and SFs and a third major site in the C-shaped cavity of SFs. In addition, we report that tau filaments from posterior cortical atrophy (PCA) and primary age-related tauopathy (PART) are identical to those from AD. In support, fluorescence labelling showed binding of APN-1607 to intraneuronal inclusions in AD, PART and PCA. Knowledge of the binding modes of APN-1607 to tau filaments may lead to the development of new ligands with increased specificity and binding activity. We show that cryo-EM can be used to identify the binding sites of small molecules in amyloid filaments.
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| Cryo-EM structures of tau filaments from Alzheimer's disease with PET ligand APN-1607.,Shi Y, Murzin AG, Falcon B, Epstein A, Machin J, Tempest P, Newell KL, Vidal R, Garringer HJ, Sahara N, Higuchi M, Ghetti B, Jang MK, Scheres SHW, Goedert M Acta Neuropathol. 2021 Mar 16. pii: 10.1007/s00401-021-02294-3. doi:, 10.1007/s00401-021-02294-3. PMID:33723967<ref>PMID:33723967</ref>
| | ==See Also== |
| | | *[[Microtubule-associated protein 3D structures|Microtubule-associated protein 3D structures]] |
| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
| | *[[Tau protein 3D structures|Tau protein 3D structures]] |
| </div>
| |
| <div class="pdbe-citations 7nrx" style="background-color:#fffaf0;"></div>
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| == References ==
| |
| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Homo sapiens]]
| |
| [[Category: Large Structures]] | | [[Category: Large Structures]] |
| [[Category: Epstein, A]] | | [[Category: Epstein A]] |
| [[Category: Falcon, B]] | | [[Category: Falcon B]] |
| [[Category: Garringer, H J]] | | [[Category: Garringer HJ]] |
| [[Category: Ghetti, B]] | | [[Category: Ghetti B]] |
| [[Category: Goedert, M]] | | [[Category: Goedert M]] |
| [[Category: Higuchi, M]] | | [[Category: Higuchi M]] |
| [[Category: Jang, M]] | | [[Category: Jang M]] |
| [[Category: Machin, J]] | | [[Category: Machin J]] |
| [[Category: Murzin, A G]] | | [[Category: Murzin AG]] |
| [[Category: Newell, K L]] | | [[Category: Newell KL]] |
| [[Category: Sahara, N]] | | [[Category: Sahara N]] |
| [[Category: Scheres, S H.W]] | | [[Category: Scheres SHW]] |
| [[Category: Shi, Y]] | | [[Category: Shi Y]] |
| [[Category: Tempest, P]] | | [[Category: Tempest P]] |
| [[Category: Vidal, R]] | | [[Category: Vidal R]] |
| [[Category: Positron emission tomography]]
| |
| [[Category: Protein fibril]]
| |
| [[Category: Tau filament]]
| |