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- PDB-7u18: TMEM106B(120-254) T185S protofilament from frontotemporal lobar d... -

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Basic information

Entry
Database: PDB / ID: 7u18
TitleTMEM106B(120-254) T185S protofilament from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (all cases combined).
ComponentsTMEM106B protein
KeywordsUNKNOWN FUNCTION / TMEM106B / Amyloid fibril
Function / homology
Function and homology information


lysosome localization / lysosomal transport / dendrite morphogenesis / lysosome organization / late endosome membrane / lysosomal membrane / plasma membrane
Similarity search - Function
: / : / Transmembrane protein 106 N-terminal region / Transmembrane protein 106 / TM106 protein C-terminal domain
Similarity search - Domain/homology
Transmembrane protein 106B
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 2.7 Å
AuthorsFitzpatrick, A.W.P. / Stowell, M.H.B. / Chang, A. / Xiang, X. / Wang, J. / Lee, C. / Arakhamia, T. / Simjanoska, M. / Wang, C. / Carlomagno, Y. ...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.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)UO1NS110438 United States
CitationJournal: Cell / Year: 2022
Title: Homotypic fibrillization of TMEM106B across diverse neurodegenerative diseases.
Authors: Andrew Chang / Xinyu Xiang / Jing Wang / Carolyn Lee / Tamta Arakhamia / Marija Simjanoska / Chi Wang / Yari Carlomagno / Guoan Zhang / Shikhar Dhingra / Manon Thierry / Jolien Perneel / ...Authors: Andrew Chang / Xinyu Xiang / Jing Wang / Carolyn Lee / Tamta Arakhamia / Marija Simjanoska / Chi Wang / Yari Carlomagno / Guoan Zhang / Shikhar Dhingra / Manon Thierry / Jolien Perneel / Bavo Heeman / Lauren M Forgrave / Michael DeTure / Mari L DeMarco / Casey N Cook / Rosa Rademakers / Dennis W Dickson / Leonard Petrucelli / Michael H B Stowell / Ian R A Mackenzie / Anthony W P Fitzpatrick /
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 ...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.
History
DepositionFeb 20, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 23, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 30, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature
Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: TMEM106B protein
B: TMEM106B protein
C: TMEM106B protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,12015
Polymers46,4663
Non-polymers2,65412
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein TMEM106B protein


Mass: 15488.652 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TMEM106B / Production host: Homo sapiens (human) / References: UniProt: Q8N353
#2: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: TMEM106B(120-254) T185S protofilament from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) type A (all cases combined).
Type: COMPLEX / Entity ID: #1 / Source: NATURAL
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2800 nm / Nominal defocus min: 1400 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -0.4 ° / Axial rise/subunit: 4.8 Å / Axial symmetry: C1
3D reconstructionResolution: 2.7 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 55000 / Symmetry type: HELICAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0033516
ELECTRON MICROSCOPYf_angle_d0.5444788
ELECTRON MICROSCOPYf_dihedral_angle_d12.821531
ELECTRON MICROSCOPYf_chiral_restr0.054606
ELECTRON MICROSCOPYf_plane_restr0.004579

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