7U12

TMEM106B(120-254) singlet amyloid fibril from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (case 2)

Summary for 7U12

• Entry DOI: 10.2210/pdb7u12/pdb
• EMDB information: 26268 26273 26274 26275 26276
• Descriptor: Transmembrane protein 106B, 2-acetamido-2-deoxy-beta-D-glucopyranose (2 entities in total)
• Functional Keywords: tmem106b, amyloid fibril, protein fibril
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 3
• Total formula weight: 49162.54

Authors

Fitzpatrick, A.W.P.,Stowell, M.H.B.,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, L.M.,DeTure, M.,DeMarco, M.L.,Cook, C.N.,Rademakers, R.,Dickson, D.,Petrucelli, L.,Mackenzie, I.R.A. (deposition date: 2022-02-19, release date: 2022-03-23, Last modification date: 2022-04-27)

Primary citation

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, L.M.,DeTure, M.,DeMarco, M.L.,Cook, C.N.,Rademakers, R.,Dickson, D.W.,Petrucelli, L.,Stowell, M.H.B.,Mackenzie, I.R.A.,Fitzpatrick, A.W.P.
Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.
Cell, 185:1346-1355.e15, 2022

PubMed Abstract: 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 α-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 Å 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.

PubMed: 35247328
DOI: 10.1016/j.cell.2022.02.026

Experimental method

ELECTRON MICROSCOPY (3.5 Å)