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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
Sample
  • Complex: hIAPP fibril
    • Protein or peptide: Islet amyloid polypeptide
KeywordshIAPP / type II diabetes / amyloid / PROTEIN FIBRIL
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 / negative regulation of osteoclast differentiation / Regulation of gene expression in beta cells ...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 / negative regulation of osteoclast differentiation / Regulation of gene expression in beta cells / positive regulation of cAMP/PKA signal transduction / 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 / apoptotic process / lipid binding / 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
AuthorsCao Q / Boyer DR
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-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing 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.)-0.000000000005742 (±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
Components
  • Complex: hIAPP fibril
    • Protein or peptide: Islet amyloid polypeptide

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Supramolecule #1: hIAPP fibril

SupramoleculeName: hIAPP fibril / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Details: Synthetic hIAPP seeded by hIAPP fibrils extracted from a patient with Type II Diabetes
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 / Number of copies: 10 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.907312 KDa
SequenceString:
KCNTATCATQ RLANFLVHSS 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

BufferpH: 7.4 / Details: PBS buffer
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 120 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Detector mode: SUPER-RESOLUTION / Number grids imaged: 3 / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionApplied symmetry - Helical parameters - Δz: 4.8 Å
Applied symmetry - Helical parameters - Δ&Phi: 178.42 °
Applied symmetry - Helical parameters - Axial symmetry: C2 (2 fold cyclic)
Resolution.type: BY AUTHOR / Resolution: 3.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 2) / Number images used: 23957
Startup modelType of model: NONE
Final angle assignmentType: NOT APPLICABLE / Software - Name: RELION (ver. 2)
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: AB INITIO MODEL / Overall B value: 98
Output model

PDB-7m62:
Cryo-EM structure of human islet amyloid polypeptide (hIAPP, or amylin) fibrils seeded by patient extracted fibrils, polymorph 2

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