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- EMDB-76248: Structure of TMEM106B singlet from patient brain derived lysosomes -

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Basic information

Entry
Database: EMDB / ID: EMD-76248
TitleStructure of TMEM106B singlet from patient brain derived lysosomes
Map dataSharpened map from post-processing with mask
Sample
  • Complex: TMEM106B doublet
Keywordsamyloid / lysosomal protein / protein aggregates / FTLD / PROTEIN FIBRIL
Biological speciesHomo sapiens (human)
Methodsubtomogram averaging / cryo EM / Resolution: 37.0 Å
AuthorsFernandez MF / Mosalaganti S
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)DP2150019 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)S10OD030275 United States
CitationJournal: bioRxiv / Year: 2026
Title: Neurodegeneration risk variants promote lysosomal TMEM106B fibril accumulation.
Authors: John Michael Replogle / Jordan D Marks / Martin G Fernandez / Hebao Yuan / Dahyun Yu / Elizabeth Winters / Vidhya Maheswari Jawahar / Rishi Deshmukh / Renaldo Sutanto / Isabelle Kowal / ...Authors: John Michael Replogle / Jordan D Marks / Martin G Fernandez / Hebao Yuan / Dahyun Yu / Elizabeth Winters / Vidhya Maheswari Jawahar / Rishi Deshmukh / Renaldo Sutanto / Isabelle Kowal / Ashley Frankenfield / Rachel Shi / Yari Carlomagno / Karen Jansen-West / Tiffany W Todd / Andrii Kopach / Iradukunda Sandra Ndayambaje / Yue A Qi / Ananth Shantaraman / Ignacio Pozo-Cabanell / Udit Sheth / Mei Yue / Duc Duong / Shawn M Ferguson / David A Bennett / Markus Damme / Brad F Boeve / Gregory S Day / Benjamin Kellman / William C Skarnes / Ronald C Petersen / Keith A Josephs / Neill R Graff-Radford / Justin A McDonough / Mercedes Prudencio / Sami J Barmada / Yongjie Zhang / Ling Hao / Michael DeTure / Bailey Rawlinson / Erica Engelberg-Cook / Monica Castanedes Casey / Nathan Perez / Dennis W Dickson / Aliza Wingo / Yue Liu / Nicholas T Seyfried / Thomas S Wingo / Shyamal Mosalaganti / Leonard Petrucelli / Michael E Ward /
Abstract: Variants in and , which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants ...Variants in and , which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding risk variant (p.T185) drives fibril core accumulation by impairing its degradation and risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In -mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.
History
DepositionMar 21, 2026-
Header (metadata) releaseApr 22, 2026-
Map releaseApr 22, 2026-
UpdateApr 22, 2026-
Current statusApr 22, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_76248.png

Downloads & links

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Map

FileDownload / File: emd_76248.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map from post-processing with mask
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
4.24 Å/pix.
x 192 pix.
= 814.08 Å		4.24 Å/pix.
x 192 pix.
= 814.08 Å		4.24 Å/pix.
x 192 pix.
= 814.08 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 4.24 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0219
Minimum - Maximum-0.00074786664 - 0.03836229
Average (Standard dev.)0.0001224613 (±0.0017982583)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions192192192
Spacing192192192
CellA=B=C: 814.07996 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_76248_msk_1.map
Projections & Slices
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Additional map: Sharpened map from post-processing without mask

Fileemd_76248_additional_1.map
AnnotationSharpened map from post-processing without mask
Projections & Slices
AxesZYX

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Half map: Output half-map #2 from 3D auto-refinement in RELION-5

Fileemd_76248_half_map_1.map
AnnotationOutput half-map #2 from 3D auto-refinement in RELION-5
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Output half-map #1 from 3D auto-refinement in RELION-5

Fileemd_76248_half_map_2.map
AnnotationOutput half-map #1 from 3D auto-refinement in RELION-5
Projections & Slices
AxesZYX

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Sample components

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Entire : TMEM106B doublet

EntireName: TMEM106B doublet
Components
  • Complex: TMEM106B doublet

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Supramolecule #1: TMEM106B doublet

SupramoleculeName: TMEM106B doublet / type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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Experimental details

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Structure determination

Methodcryo EM
Processingsubtomogram averaging
Aggregation statefilament

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 3.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 2.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.78 Å
Applied symmetry - Helical parameters - Δ&Phi: -0.41 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 37.0 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0.0) / Number subtomograms used: 4240
ExtractionNumber tomograms: 25 / Number images used: 25508 / Software: (Name: Warp, Dynamo)
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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