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- EMDB-23687: Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or a... -

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Basic information

Entry
Database: EMDB / ID: EMD-23687
TitleCryo-EM structure of human islet amyloid polypeptide (hIAPP, or amylin) fibrils seeded by patient extracted fibrils, polymorph 2
Map data
SamplehIAPP fibril:
Islet amyloid polypeptideAmylin
Function / homology
Function and homology information


positive regulation of calcium ion import across plasma membrane / Calcitonin-like ligand receptors / amylin receptor signaling pathway / eating behavior / negative regulation of amyloid fibril formation / negative regulation of mitochondrion organization / negative regulation of bone resorption / positive regulation of protein kinase A signaling / Regulation of gene expression in beta cells / negative regulation of protein-containing complex assembly ...positive regulation of calcium ion import across plasma membrane / Calcitonin-like ligand receptors / amylin receptor signaling pathway / eating behavior / negative regulation of amyloid fibril formation / negative regulation of mitochondrion organization / negative regulation of bone resorption / positive regulation of protein kinase A signaling / Regulation of gene expression in beta cells / negative regulation of protein-containing complex assembly / negative regulation of cell differentiation / inclusion body / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating G protein-coupled receptor signaling pathway / sensory perception of pain / positive regulation of cell death / G alpha (s) signalling events / protein destabilization / protein homooligomerization / hormone activity / cell-cell signaling / negative regulation of inflammatory response to antigenic stimulus / amyloid-beta binding / positive regulation of cytosolic calcium ion concentration / positive regulation of MAPK cascade / positive regulation of peptidyl-serine phosphorylation / positive regulation of ERK1 and ERK2 cascade / positive regulation of protein kinase B signaling / Amyloid fiber formation / negative regulation of cell population proliferation / G protein-coupled receptor signaling pathway / amyloid fibril formation / positive regulation of apoptotic process / signaling receptor binding / neuronal cell body / apoptotic process / positive regulation of gene expression / signal transduction / extracellular space / extracellular region / identical protein binding
Similarity search - Function
Islet amyloid polypeptide / calcitonin / Calcitonin, conserved site / Calcitonin peptide-like / Calcitonin / CGRP / IAPP family signature. / Calcitonin-like / 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
AuthorsCao Q / Boyer DR / Sawaya MR / Eisenberg DS
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute on Aging (NIH/NIA)AG0543022 United States
CitationJournal: Nat Struct Mol Biol / Year: 2021
Title: Cryo-EM structures of hIAPP fibrils seeded by patient-extracted fibrils reveal new polymorphs and conserved fibril cores.
Authors: Qin Cao / David R Boyer / Michael R Sawaya / Romany Abskharon / Lorena Saelices / Binh A Nguyen / Jiahui Lu / Kevin A Murray / Fouad Kandeel / David S Eisenberg /
Abstract: Amyloidosis of human islet amyloid polypeptide (hIAPP) is a pathological hallmark of type II diabetes (T2D), an epidemic afflicting nearly 10% of the world's population. To visualize disease-relevant ...Amyloidosis of human islet amyloid polypeptide (hIAPP) is a pathological hallmark of type II diabetes (T2D), an epidemic afflicting nearly 10% of the world's population. To visualize disease-relevant hIAPP fibrils, we extracted amyloid fibrils from islet cells of a T2D donor and amplified their quantity by seeding synthetic hIAPP. Cryo-EM studies revealed four fibril polymorphic atomic structures. Their resemblance to four unseeded hIAPP fibrils varies from nearly identical (TW3) to non-existent (TW2). The diverse repertoire of hIAPP polymorphs appears to arise from three distinct protofilament cores entwined in different combinations. The structural distinctiveness of TW1, TW2 and TW4 suggests they may be faithful replications of the pathogenic seeds. If so, the structures determined here provide the most direct view yet of hIAPP amyloid fibrils formed during T2D.
History
DepositionMar 25, 2021-
Header (metadata) releaseSep 22, 2021-
Map releaseSep 22, 2021-
UpdateSep 22, 2021-
Current statusSep 22, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 2.5
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 2.5
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7m62
  • Surface level: 2.5
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7m62
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_23687.png

Downloads & links

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Map

FileDownload / File: emd_23687.map.gz / Format: CCP4 / Size: 8 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.06 Å/pix.
x 128 pix.
= 135.04 Å		1.06 Å/pix.
x 128 pix.
= 135.04 Å		1.06 Å/pix.
x 128 pix.
= 135.04 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.055 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 2.0 / Movie #1: 2.5
Minimum - Maximum-2.2545238 - 6.300957
Average (Standard dev.)-5.74165e-12 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin-64-64-64
Dimensions128128128
Spacing128128128
CellA=B=C: 135.04 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0551.0551.055
M x/y/z128128128
origin x/y/z0.0000.0000.000
length x/y/z135.040135.040135.040
α/β/γ90.00090.00090.000
start NX/NY/NZ-64-64-64
NX/NY/NZ128128128
MAP C/R/S321
start NC/NR/NS-64-64-64
NC/NR/NS128128128
D min/max/mean-2.2556.301-0.000

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Supplemental data

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Sample components

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Entire hIAPP fibril

EntireName: hIAPP fibril
Details: Synthetic hIAPP seeded by hIAPP fibrils extracted from a patient with Type II Diabetes
Number of Components: 2

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Component #1: protein, hIAPP fibril

ProteinName: hIAPP fibril
Details: Synthetic hIAPP seeded by hIAPP fibrils extracted from a patient with Type II Diabetes
Recombinant expression: No
SourceSpecies: Homo sapiens (human)

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Component #2: protein, Islet amyloid polypeptide

ProteinName: Islet amyloid polypeptideAmylin / Number of Copies: 10 / Recombinant expression: No
MassTheoretical: 3.907312 kDa
SourceSpecies: Homo sapiens (human)

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Experimental details

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Sample preparation

SpecimenSpecimen State: Filament / Method: cryo EM
Helical ParametersAxial Symmetry: C2 (2 fold cyclic) / Delta Z: 4.8 Å / Delta Phi: 178.42 %deg;
Sample solutionBuffer solution: PBS buffer / pH: 7.4
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen Name: ETHANE / Temperature: 298 K / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron Source: FIELD EMISSION GUN / Accelerating Voltage: 300 kV / Electron Dose: 45 e/Å2 / Illumination Mode: FLOOD BEAM
LensImaging Mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: OTHER

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Image processing

ProcessingMethod: helical reconstruction
3D reconstructionSoftware: RELION / Resolution: 3.9 Å / Resolution Method: FSC 0.143 CUT-OFF
FSC plot (resolution estimation)

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Atomic model buiding

Modeling #1Refinement space: REAL / Overall BValue: 98
Output model

7m62

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