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- EMDB-24953: Cryo-EM structure of TMEM106B fibrils extracted from a FTLD-TDP p... -

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Basic information

Entry
Database: EMDB / ID: EMD-24953
TitleCryo-EM structure of TMEM106B fibrils extracted from a FTLD-TDP patient, polymorph 1
Map data
Sample
  • Organelle or cellular component: TMEM106B fibrils, polymorph 1
    • Protein or peptide: Transmembrane protein 106B
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsTMEM106B / FTLD-TDP / amyloid / PROTEIN FIBRIL
Function / homology
Function and homology information


lysosomal protein catabolic process / regulation of lysosome organization / lysosomal lumen acidification / lysosome localization / positive regulation of dendrite development / dendrite morphogenesis / lysosomal transport / lysosome organization / neuron cellular homeostasis / late endosome membrane ...lysosomal protein catabolic process / regulation of lysosome organization / lysosomal lumen acidification / lysosome localization / positive regulation of dendrite development / dendrite morphogenesis / lysosomal transport / lysosome organization / neuron cellular homeostasis / late endosome membrane / ATPase binding / lysosome / endosome / lysosomal membrane / plasma membrane
Similarity search - Function
Transmembrane protein 106 / : / : / TM106 protein C-terminal domain / Transmembrane protein 106 N-terminal region
Similarity search - Domain/homology
Transmembrane protein 106B
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsCao Q / Jiang Y
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG0543022 United States
CitationJournal: Nature / Year: 2022
Title: Amyloid fibrils in FTLD-TDP are composed of TMEM106B and not TDP-43.
Authors: Yi Xiao Jiang / Qin Cao / Michael R Sawaya / Romany Abskharon / Peng Ge / Michael DeTure / Dennis W Dickson / Janine Y Fu / Rachel R Ogorzalek Loo / Joseph A Loo / David S Eisenberg /
Abstract: Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative condition after Alzheimer's and Parkinson's diseases. FTLD typically presents in 45 to 64 year olds with ...Frontotemporal lobar degeneration (FTLD) is the third most common neurodegenerative condition after Alzheimer's and Parkinson's diseases. FTLD typically presents in 45 to 64 year olds with behavioural changes or progressive decline of language skills. The subtype FTLD-TDP is characterized by certain clinical symptoms and pathological neuronal inclusions with TAR DNA-binding protein (TDP-43) immunoreactivity. Here we extracted amyloid fibrils from brains of four patients representing four of the five FTLD-TDP subclasses, and determined their structures by cryo-electron microscopy. Unexpectedly, all amyloid fibrils examined were composed of a 135-residue carboxy-terminal fragment of transmembrane protein 106B (TMEM106B), a lysosomal membrane protein previously implicated as a genetic risk factor for FTLD-TDP. In addition to TMEM106B fibrils, we detected abundant non-fibrillar aggregated TDP-43 by immunogold labelling. Our observations confirm that FTLD-TDP is associated with amyloid fibrils, and that the fibrils are formed by TMEM106B rather than TDP-43.
History
DepositionSep 23, 2021-
Header (metadata) releaseMar 9, 2022-
Map releaseMar 9, 2022-
UpdateNov 20, 2024-
Current statusNov 20, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7saq
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24953.png

Downloads & links

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Map

FileDownload / File: emd_24953.map.gz / Format: CCP4 / Size: 7.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.1 Å/pix.
x 50 pix.
= 55. Å		1.1 Å/pix.
x 200 pix.
= 220. Å		1.1 Å/pix.
x 200 pix.
= 220. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX=Y=Z: 1.1 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03 / Movie #1: 0.03
Minimum - Maximum-0.09226221 - 0.16010556
Average (Standard dev.)0.00057341286 (±0.011471644)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-100-100-25
Dimensions20020050
Spacing20020050
CellA: 220.0 Å / B: 220.0 Å / C: 55.0 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.11.11.1
M x/y/z20020050
origin x/y/z0.0000.0000.000
length x/y/z220.000220.00055.000
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ368368368
MAP C/R/S123
start NC/NR/NS-100-100-25
NC/NR/NS20020050
D min/max/mean-0.0920.1600.001

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Supplemental data

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Sample components

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Entire : TMEM106B fibrils, polymorph 1

EntireName: TMEM106B fibrils, polymorph 1
Components
  • Organelle or cellular component: TMEM106B fibrils, polymorph 1
    • Protein or peptide: Transmembrane protein 106B
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: TMEM106B fibrils, polymorph 1

SupramoleculeName: TMEM106B fibrils, polymorph 1 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: #1
Details: Amyloid fibrils extracted from autopsied brain tissues of a donor with FTLD-TDP
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Transmembrane protein 106B

MacromoleculeName: Transmembrane protein 106B / type: protein_or_peptide / ID: 1
Details: Glycosylation of Asn145, Asn151, Asn164, and Asn183
Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 31.156318 KDa
SequenceString: MGKSLSHLPL HSSKEDAYDG VTSENMRNGL VNSEVHNEDG RNGDVSQFPY VEFTGRDSVT CPTCQGTGRI PRGQENQLVA LIPYSDQRL RPRRTKLYVM ASVFVCLLLS GLAVFFLFPR SIDVKYIGVK SAYVSYDVQK RTIYLNITNT LNITNNNYYS V EVENITAQ ...String:
MGKSLSHLPL HSSKEDAYDG VTSENMRNGL VNSEVHNEDG RNGDVSQFPY VEFTGRDSVT CPTCQGTGRI PRGQENQLVA LIPYSDQRL RPRRTKLYVM ASVFVCLLLS GLAVFFLFPR SIDVKYIGVK SAYVSYDVQK RTIYLNITNT LNITNNNYYS V EVENITAQ VQFSKTVIGK ARLNNITIIG PLDMKQIDYT VPTVIAEEMS YMYDFCTLIS IKVHNIVLMM QVTVTTTYFG HS EQISQER YQYVDCGRNT TYQLGQSEYL NVLQPQQ

UniProtKB: Transmembrane protein 106B

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Macromolecule #2: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 20 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: SUPER-RESOLUTION / Number grids imaged: 1 / Average electron dose: 39.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.91 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.42 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3) / Number images used: 60806
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 2)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL / Overall B value: 124
Output model

PDB-7saq:
Cryo-EM structure of TMEM106B fibrils extracted from a FTLD-TDP patient, polymorph 1

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