Proteopedia

7u14

Revision as of 14:56, 27 April 2022 by OCA (talk | contribs)

TMEM106B(120-254) singlet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type C (case 8)TMEM106B(120-254) singlet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type C (case 8)

Structural highlights

7u14 is a 3 chain structure. 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

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[7]

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

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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

7u14, resolution 4.50Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=7u14&oldid=3552840"