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- PDB-6y1a: Amyloid fibril structure of islet amyloid polypeptide -

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Basic information

Entry
Database: PDB / ID: 6y1a
TitleAmyloid fibril structure of islet amyloid polypeptide
ComponentsIslet amyloid polypeptide
KeywordsHORMONE / amylin / iapp / amyloid fibril / diabetes
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
AMINO GROUP / Islet amyloid polypeptide
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / helical reconstruction / cryo EM / Resolution: 4.2 Å
AuthorsRoeder, C. / Kupreichyk, T. / Gremer, L. / Schaefer, L.U. / Pothula, K.R. / Ravelli, R.B.G. / Willbold, D. / Hoyer, W. / Schroder, G.F.
Funding supportEuropean Union, 1items
OrganizationGrant numberCountry
European Research Council (ERC)726368European Union
Citation
Journal: Nat Struct Mol Biol / Year: 2020
Title: Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils.
Authors: Christine Röder / Tatsiana Kupreichyk / Lothar Gremer / Luisa U Schäfer / Karunakar R Pothula / Raimond B G Ravelli / Dieter Willbold / Wolfgang Hoyer / Gunnar F Schröder /
Abstract: Amyloid deposits consisting of fibrillar islet amyloid polypeptide (IAPP) in pancreatic islets are associated with beta-cell loss and have been implicated in type 2 diabetes (T2D). Here, we applied ...Amyloid deposits consisting of fibrillar islet amyloid polypeptide (IAPP) in pancreatic islets are associated with beta-cell loss and have been implicated in type 2 diabetes (T2D). Here, we applied cryo-EM to reconstruct densities of three dominant IAPP fibril polymorphs, formed in vitro from synthetic human IAPP. An atomic model of the main polymorph, built from a density map of 4.2-Å resolution, reveals two S-shaped, intertwined protofilaments. The segment 21-NNFGAIL-27, essential for IAPP amyloidogenicity, forms the protofilament interface together with Tyr37 and the amidated C terminus. The S-fold resembles polymorphs of Alzheimer's disease (AD)-associated amyloid-β (Aβ) fibrils, which might account for the epidemiological link between T2D and AD and reports on IAPP-Aβ cross-seeding in vivo. The results structurally link the early-onset T2D IAPP genetic polymorphism (encoding Ser20Gly) with the AD Arctic mutation (Glu22Gly) of Aβ and support the design of inhibitors and imaging probes for IAPP fibrils.
#1: Journal: Biorxiv / Year: 2020
Title: Amyloid fibril structure of islet amyloid polypeptide by cryo-electron microscopy reveals similarities with amyloid beta
Authors: Roeder, C. / Kupreichyk, T. / Gremer, L. / Schaefer, L.U. / Pothula, K.R. / Ravelli, R.B.G. / Willbold, D. / Hoyer, W. / Schroder, G.F.
History
DepositionFeb 11, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 4, 2020Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2020Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2020Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2020Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2020Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
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Revision 1.0Mar 4, 2020Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2020Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2020Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2020Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 4, 2020Data content type: Mask / Part number: 1 / Data content type: Mask / Provider: repository / Type: Initial release
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Revision 1.1Jul 22, 2020Group: Database references / Category: citation / citation_author
Revision 1.2Apr 9, 2025Group: Data collection / Database references / Structure summary
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Assembly

Deposited unit
A: Islet amyloid polypeptide
B: Islet amyloid polypeptide
C: Islet amyloid polypeptide
D: Islet amyloid polypeptide
E: Islet amyloid polypeptide
F: Islet amyloid polypeptide
G: Islet amyloid polypeptide
H: Islet amyloid polypeptide
I: Islet amyloid polypeptide
J: Islet amyloid polypeptide
K: Islet amyloid polypeptide
L: Islet amyloid polypeptide
M: Islet amyloid polypeptide
N: Islet amyloid polypeptide
O: Islet amyloid polypeptide
P: Islet amyloid polypeptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,80532
Polymers62,54916
Non-polymers25616
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: scanning transmission electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area35890 Å2
ΔGint-121 kcal/mol
Surface area12040 Å2

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Components

#1: Protein/peptide
Islet amyloid polypeptide / Amylin / Diabetes-associated peptide / DAP / Insulinoma amyloid peptide


Mass: 3909.304 Da / Num. of mol.: 16 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: P10997
#2: Chemical
ChemComp-NH2 / AMINO GROUP


Mass: 16.023 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: NH2
Has ligand of interestN
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: FILAMENT / 3D reconstruction method: helical reconstruction

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Sample preparation

ComponentName: Amyloid fibril of the islet amyloid polypeptide (IAPP)
Type: COMPLEX / Details: The fibril consists of IAPP monomers. / Entity ID: #1 / Source: NATURAL
Molecular weightValue: 10.6 kDa/nm / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Buffer solutionpH: 6
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TECNAI ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingAverage exposure time: 46 sec. / Electron dose: 41.4 e/Å2 / Detector mode: COUNTING / Film or detector model: FEI FALCON III (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 1330
EM imaging opticsPhase plate: OTHER

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Processing

EM software
IDNameVersionCategory
2EPU1.5.1.50image acquisition
12RELION3.0.53D reconstruction
13PHENIX1.11model refinement
CTF correctionType: NONE
Helical symmertyAngular rotation/subunit: 178.23 ° / Axial rise/subunit: 2.351 Å / Axial symmetry: C1
3D reconstructionResolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 37120
Details: the data set was split by whole fibrils and then refined independently for 25 iterations to yield the two half maps.
Num. of class averages: 1 / Symmetry type: HELICAL
Atomic model buildingProtocol: AB INITIO MODEL / Space: REAL

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