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.
EMPIAR-11093 (Title: Micrographs of IAPP (amylin) amyloid fibrils / Data size: 83.1 Data #1: MotionCor2-aligned single frame of islet amyloid polypeptide fibrils [micrographs - single frame])
Cryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV
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Electron microscopy
Microscope
FEI TECNAI ARCTICA
Specialist optics
Phase plate: OTHER
Image recording
Film or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 1330 / Average exposure time: 46.0 sec. / Average electron dose: 41.4 e/Å2
Electron beam
Acceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron optics
Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
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Image processing
Final reconstruction
Number classes used: 1 Applied symmetry - Helical parameters - Δz: 2.351 Å Applied symmetry - Helical parameters - Δ&Phi: 178.23 ° Applied symmetry - Helical parameters - Axial symmetry: C1 (asymmetric) Resolution.type: BY AUTHOR / Resolution: 4.2 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0.5) Details: the data set was split by whole fibrils and then refined independently for 25 iterations to yield the two half maps. Number images used: 37120
Startup model
Type of model: OTHER / Details: noise filled cylinder
Final angle assignment
Type: NOT APPLICABLE
FSC plot (resolution estimation)
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Atomic model buiding 1
Refinement
Space: REAL / Protocol: AB INITIO MODEL
Output model
PDB-6y1a: Amyloid fibril structure of islet amyloid polypeptide
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