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- EMDB-11382: two-protofilament amyloid structure of S20G variant of human amyl... -

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Basic information

Entry
Database: EMDB / ID: EMD-11382
Titletwo-protofilament amyloid structure of S20G variant of human amylin (IAPP - islet amyloid polypeptide)
Map data
Sample
  • Complex: two-protofilament amyloid fibrils of S20G variant of amylin
    • Complex: two-protofilament amyloid fibrils of S20G variant of amylin
      • Protein or peptide: Islet amyloid polypeptide
Function / homology
Function and homology information


amylin receptor 3 signaling pathway / amylin receptor 2 signaling pathway / amylin receptor 1 signaling pathway / amylin receptor signaling pathway / Calcitonin-like ligand receptors / negative regulation of amyloid fibril formation / negative regulation of bone resorption / eating behavior / positive regulation of cAMP/PKA signal transduction / negative regulation of osteoclast differentiation ...amylin receptor 3 signaling pathway / amylin receptor 2 signaling pathway / amylin receptor 1 signaling pathway / amylin receptor signaling pathway / Calcitonin-like ligand receptors / negative regulation of amyloid fibril formation / negative regulation of bone resorption / eating behavior / positive regulation of cAMP/PKA signal transduction / negative regulation of osteoclast differentiation / Regulation of gene expression in beta cells / bone resorption / negative regulation of protein-containing complex assembly / 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 / positive regulation of apoptotic process / receptor ligand activity / Amyloid fiber formation / signaling receptor binding / neuronal cell body / 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: 3.9 Å
AuthorsGallardo RU / Iadanza MG / Ranson NA / Radford SE
Funding support United Kingdom, 2 items
OrganizationGrant numberCountry
Wellcome TrustWT 204963 United Kingdom
Wellcome Trust108466/Z/15/Z United Kingdom
CitationJournal: Nat Struct Mol Biol / Year: 2020
Title: Fibril structures of diabetes-related amylin variants reveal a basis for surface-templated assembly.
Authors: Rodrigo Gallardo / Matthew G Iadanza / Yong Xu / George R Heath / Richard Foster / Sheena E Radford / Neil A Ranson /
Abstract: Aggregation of the peptide hormone amylin into amyloid deposits is a pathological hallmark of type-2 diabetes (T2D). While no causal link between T2D and amyloid has been established, the S20G ...Aggregation of the peptide hormone amylin into amyloid deposits is a pathological hallmark of type-2 diabetes (T2D). While no causal link between T2D and amyloid has been established, the S20G mutation in amylin is associated with early-onset T2D. Here we report cryo-EM structures of amyloid fibrils of wild-type human amylin and its S20G variant. The wild-type fibril structure, solved to 3.6-Å resolution, contains two protofilaments, each built from S-shaped subunits. S20G fibrils, by contrast, contain two major polymorphs. Their structures, solved at 3.9-Å and 4.0-Å resolution, respectively, share a common two-protofilament core that is distinct from the wild-type structure. Remarkably, one polymorph contains a third subunit with another, distinct, cross-β conformation. The presence of two different backbone conformations within the same fibril may explain the increased aggregation propensity of S20G, and illustrates a potential structural basis for surface-templated fibril assembly.
History
DepositionJul 14, 2020-
Header (metadata) releaseSep 30, 2020-
Map releaseSep 30, 2020-
UpdateNov 18, 2020-
Current statusNov 18, 2020Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.035
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.035
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6zrq
  • Surface level: 0.035
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_11382.png

Downloads & links

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Map

FileDownload / File: emd_11382.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 300 pix.
= 319.5 Å		1.07 Å/pix.
x 300 pix.
= 319.5 Å		1.07 Å/pix.
x 300 pix.
= 319.5 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.065 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.035 / Movie #1: 0.035
Minimum - Maximum-0.03146062 - 0.07694056
Average (Standard dev.)0.0000646648 (±0.0012930926)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 319.50003 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0651.0651.065
M x/y/z300300300
origin x/y/z0.0000.0000.000
length x/y/z319.500319.500319.500
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS300300300
D min/max/mean-0.0310.0770.000

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Supplemental data

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Sample components

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Entire : two-protofilament amyloid fibrils of S20G variant of amylin

EntireName: two-protofilament amyloid fibrils of S20G variant of amylin
Components
  • Complex: two-protofilament amyloid fibrils of S20G variant of amylin
    • Complex: two-protofilament amyloid fibrils of S20G variant of amylin
      • Protein or peptide: Islet amyloid polypeptide

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Supramolecule #1: two-protofilament amyloid fibrils of S20G variant of amylin

SupramoleculeName: two-protofilament amyloid fibrils of S20G variant of amylin
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all

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Supramolecule #2: two-protofilament amyloid fibrils of S20G variant of amylin

SupramoleculeName: two-protofilament amyloid fibrils of S20G variant of amylin
type: complex / ID: 2 / Parent: 1 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: synthetic construct (others)

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Macromolecule #1: Islet amyloid polypeptide

MacromoleculeName: Islet amyloid polypeptide / type: protein_or_peptide / ID: 1 / Details: TYC = C-terminal amidated Tyr / Number of copies: 12 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.878293 KDa
SequenceString:
KCNTATCATQ RLANFLVHSG NNFGAILSST NVGSNT(TYC)

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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: NH4CH3CO / Component - Name: ammonium acetate
GridModel: Homemade / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING
VitrificationCryogen name: ETHANE / Chamber humidity: 85 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV
DetailsSynthetically produced, oxidised and C-terminally amidated

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Average exposure time: 13.0 sec. / Average electron dose: 54.73 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionNumber classes used: 1
Applied symmetry - Helical parameters - Δz: 2.41 Å
Applied symmetry - Helical parameters - Δ&Phi: 179.05 °
Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric)
Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Number images used: 11901
CTF correctionSoftware - Name: Gctf (ver. 1.18)
Segment selectionNumber selected: 64274 / Software - Name: RELION (ver. 3.0)
Startup modelType of model: INSILICO MODEL
In silico model: model generated with relion v3.1 based on 2D class averages
Final angle assignmentType: NOT APPLICABLE
FSC plot (resolution estimation)

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