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- PDB-7saq: Cryo-EM structure of TMEM106B fibrils extracted from a FTLD-TDP p... -

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Basic information

Entry
Database: PDB / ID: 7saq
TitleCryo-EM structure of TMEM106B fibrils extracted from a FTLD-TDP patient, polymorph 1
ComponentsTransmembrane protein 106BTransmembrane protein
KeywordsPROTEIN FIBRIL / TMEM106B / FTLD-TDP / amyloid
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 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: 2.9 Å
AuthorsCao, Q. / Jiang, Y. / Sawaya, M.R. / Eisenberg, D.S.
Funding support United States, 1items
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, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2022Provider: repository / Type: Initial release
Revision 1.1May 4, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2May 18, 2022Group: Database references / Category: citation / citation_author / Item: _citation.title / _citation_author.identifier_ORCID
Revision 1.3May 25, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Assembly

Deposited unit
A: Transmembrane protein 106B
B: Transmembrane protein 106B
C: Transmembrane protein 106B
D: Transmembrane protein 106B
E: Transmembrane protein 106B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)160,20625
Polymers155,7825
Non-polymers4,42420
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area53900 Å2
ΔGint-20 kcal/mol
Surface area29600 Å2

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Components

#1: Protein
Transmembrane protein 106B / Transmembrane protein


Mass: 31156.318 Da / Num. of mol.: 5 / Source method: isolated from a natural source
Details: Glycosylation of Asn145, Asn151, Asn164, and Asn183
Source: (natural) Homo sapiens (human) / References: UniProt: Q9NUM4
#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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 20 / Source method: obtained synthetically / Formula: C8H15NO6
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 interestN

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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 fibrils, polymorph 1 / Type: ORGANELLE OR CELLULAR COMPONENT
Details: Amyloid fibrils extracted from autopsied brain tissues of a donor with FTLD-TDP
Entity ID: #1 / Source: NATURAL
Molecular weightUnits: KILODALTONS/NANOMETER / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 298 K

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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 FIELDBright-field microscopy
Image recordingElectron dose: 39 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1

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Processing

EM software
IDNameVersionCategory
1crYOLOparticle selection
2Leginonimage acquisition
4CTFFIND4.1.8CTF correction
7PHENIXsequence_from_mapmodel fitting
9RELION2initial Euler assignment
10RELION2final Euler assignment
12RELION33D reconstruction
13PHENIXreal_space_refinemodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Helical symmertyAngular rotation/subunit: -0.42 ° / Axial rise/subunit: 4.91 Å / Axial symmetry: C1
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 60806 / Symmetry type: HELICAL
Atomic model buildingB value: 124 / Protocol: AB INITIO MODEL / Space: REAL

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