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- EMDB-15756: IAPP S20G plateau-phase fibril polymorph 4PF-LJ -

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Basic information

Entry
Database: EMDB / ID: EMD-15756
TitleIAPP S20G plateau-phase fibril polymorph 4PF-LJ
Map dataCryoEM map for 22-week aged IAPP-S20G 4PF-LJ fibrils
Sample
  • Complex: IAPP S20G plateau-phase fibril polymorph 4PF-LJ
    • Protein or peptide: Islet amyloid polypeptide
KeywordsAmyloid / fibril / helical / cross-beta / Amylin / polymorph / islet / PROTEIN FIBRIL / Diabetes
Function / homology
Function and homology information


amylin receptor signaling pathway / Calcitonin-like ligand receptors / negative regulation of amyloid fibril formation / negative regulation of bone resorption / eating behavior / positive regulation of protein kinase A signaling / negative regulation of osteoclast differentiation / Regulation of gene expression in beta cells / negative regulation of protein-containing complex assembly / bone resorption ...amylin receptor signaling pathway / Calcitonin-like ligand receptors / negative regulation of amyloid fibril formation / negative regulation of bone resorption / eating behavior / positive regulation of protein kinase A signaling / negative regulation of osteoclast differentiation / Regulation of gene expression in beta cells / negative regulation of protein-containing complex assembly / bone resorption / sensory perception of pain / positive regulation of calcium-mediated signaling / osteoclast differentiation / hormone activity / cell-cell signaling / amyloid-beta binding / G alpha (s) signalling events / positive regulation of MAPK cascade / receptor ligand activity / positive regulation of apoptotic process / Amyloid fiber formation / signaling receptor binding / lipid binding / apoptotic process / signal transduction / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Islet amyloid polypeptide / Calcitonin-like / Calcitonin peptide-like / Calcitonin, conserved site / Calcitonin / CGRP / IAPP family signature. / calcitonin / Calcitonin/adrenomedullin / Calcitonin / CGRP / IAPP family
Similarity search - Domain/homology
Islet amyloid polypeptide
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodhelical reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsWilkinson M / Xu Y / Gallardo R / Radford SE / Ranson NA
Funding support United Kingdom, 2 items
OrganizationGrant numberCountry
Wellcome Trust United Kingdom
Medical Research Council (MRC, United Kingdom) United Kingdom
CitationJournal: Cell / Year: 2023
Title: Structural evolution of fibril polymorphs during amyloid assembly.
Authors: Martin Wilkinson / Yong Xu / Dev Thacker / Alexander I P Taylor / Declan G Fisher / Rodrigo U Gallardo / Sheena E Radford / Neil A Ranson /
Abstract: Cryoelectron microscopy (cryo-EM) has provided unprecedented insights into amyloid fibril structures, including those associated with disease. However, these structures represent the endpoints of ...Cryoelectron microscopy (cryo-EM) has provided unprecedented insights into amyloid fibril structures, including those associated with disease. However, these structures represent the endpoints of long assembly processes, and their relationship to fibrils formed early in assembly is unknown. Consequently, whether different fibril architectures, with potentially different pathological properties, form during assembly remains unknown. Here, we used cryo-EM to determine structures of amyloid fibrils at different times during in vitro fibrillation of a disease-related variant of human islet amyloid polypeptide (IAPP-S20G). Strikingly, the fibrils formed in the lag, growth, and plateau phases have different structures, with new forms appearing and others disappearing as fibrillation proceeds. A time course with wild-type hIAPP also shows fibrils changing with time, suggesting that this is a general property of IAPP amyloid assembly. The observation of transiently populated fibril structures has implications for understanding amyloid assembly mechanisms with potential new insights into amyloid progression in disease.
History
DepositionSep 5, 2022-
Header (metadata) releaseJan 10, 2024-
Map releaseJan 10, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_15756.png

Downloads & links

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Map

FileDownload / File: emd_15756.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryoEM map for 22-week aged IAPP-S20G 4PF-LJ fibrils
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.9 Å/pix.
x 300 pix.
= 270. Å		0.9 Å/pix.
x 300 pix.
= 270. Å		0.9 Å/pix.
x 300 pix.
= 270. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.9 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0085
Minimum - Maximum-0.014717756 - 0.04288681
Average (Standard dev.)0.0002534699 (±0.0019316879)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 270.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: halfmap1

Fileemd_15756_half_map_1.map
Annotationhalfmap1
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: halfmap2

Fileemd_15756_half_map_2.map
Annotationhalfmap2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : IAPP S20G plateau-phase fibril polymorph 4PF-LJ

EntireName: IAPP S20G plateau-phase fibril polymorph 4PF-LJ
Components
  • Complex: IAPP S20G plateau-phase fibril polymorph 4PF-LJ
    • Protein or peptide: Islet amyloid polypeptide

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Supramolecule #1: IAPP S20G plateau-phase fibril polymorph 4PF-LJ

SupramoleculeName: IAPP S20G plateau-phase fibril polymorph 4PF-LJ / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: In vitro fibril growth for 22 weeks at room temperature
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Islet amyloid polypeptide

MacromoleculeName: Islet amyloid polypeptide / type: protein_or_peptide / ID: 1 / Details: Synthesised with C-terminal amidation / Number of copies: 20 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.877286 KDa
SequenceString:
KCNTATCATQ RLANFLVHSG NNFGAILSST NVGSNTY(NH2)

UniProtKB: Islet amyloid polypeptide

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Experimental details

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Structure determination

Methodcryo EM
Processinghelical reconstruction
Aggregation statefilament

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Sample preparation

Concentration0.12 mg/mL
BufferpH: 6.8 / Component - Concentration: 20.0 mM / Component - Formula: NH3CH3CO2 / Component - Name: ammonium acetate
GridModel: EMS Lacey Carbon / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: LACEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 60 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 90 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: 6s blot.
DetailsFibrillation conditions: 30 uM monomeric IAPP-S20G, quiescent at room temp for 22 weeks

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Number grids imaged: 1 / Number real images: 2186 / Average exposure time: 5.0 sec. / Average electron dose: 39.0 e/Å2
Details: 1204 raw EER frames were collected per image and combined into 30 fractions for processing
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 2.41 Å
Applied symmetry - Helical parameters - Δ&Phi: 178.88 °
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. 4.0) / Number images used: 28443
Segment selectionNumber selected: 1978281
Details: Manually picked a subset of images to train a model for automatic fibril segment picking in crYOLO
Startup modelType of model: INSILICO MODEL
Details: Model generated from 2D class averages using relion_helix_inimodel2d
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 4.0)

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Atomic model buiding 1

Initial modelPDB ID:

8az0


Chain - Chain ID: A / Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: AB INITIO MODEL / Overall B value: 61 / Target criteria: Correlation coefficient
Output model

PDB-8az7:
IAPP S20G plateau-phase fibril polymorph 4PF-LJ

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