Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils

Christine Roeder; Tatsiana Kupreichyk; Lothar Gremer; Luisa U. Schaefer; Karunakar R. Pothula; Raimond B. G. Ravelli; Dieter Willbold; Wolfgang Hoyer; Gunnar F. Schroeder

doi:10.1038/s41594-020-0442-4

Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils

Christine Roeder, Tatsiana Kupreichyk, Lothar Gremer, Luisa U. Schaefer, Karunakar R. Pothula, Raimond B. G. Ravelli, Dieter Willbold, Wolfgang Hoyer^*, Gunnar F. Schroeder^*

^*Corresponding author for this work

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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 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-angstrom 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-beta (A beta) fibrils, which might account for the epidemiological link between T2D and AD and reports on IAPP-A beta cross-seeding in vivo. The results structurally link the early-onset T2D IAPP genetic polymorphism (encoding Ser20Gly) with the AD Arctic mutation (Glu22Gly) of A beta and support the design of inhibitors and imaging probes for IAPP fibrils.

Cryo-EM analyses of amyloid fibrils formed by synthetic human IAPP show an S-fold for the main polymorph, with the backbone superimposable with those of amyloid-beta fibrils in antiparallel arrangement.

Original language	English
Pages (from-to)	660-+
Number of pages	18
Journal	Nature Structural and Molecular Biology
Volume	27
Issue number	7
DOIs	https://doi.org/10.1038/s41594-020-0442-4
Publication status	Published - Jul 2020

Keywords

ATOMIC-RESOLUTION STRUCTURE
ALZHEIMERS-DISEASE
S20G MUTATION
HUMAN AMYLIN
DYNAMICS
IAPP
MECHANISM
SYSTEM
GENE
CRYSTALLOGRAPHY

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Cite this

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title = "Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils",

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 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-angstrom 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-beta (A beta) fibrils, which might account for the epidemiological link between T2D and AD and reports on IAPP-A beta cross-seeding in vivo. The results structurally link the early-onset T2D IAPP genetic polymorphism (encoding Ser20Gly) with the AD Arctic mutation (Glu22Gly) of A beta and support the design of inhibitors and imaging probes for IAPP fibrils.Cryo-EM analyses of amyloid fibrils formed by synthetic human IAPP show an S-fold for the main polymorph, with the backbone superimposable with those of amyloid-beta fibrils in antiparallel arrangement.",

keywords = "ATOMIC-RESOLUTION STRUCTURE, ALZHEIMERS-DISEASE, S20G MUTATION, HUMAN AMYLIN, DYNAMICS, IAPP, MECHANISM, SYSTEM, GENE, CRYSTALLOGRAPHY",

author = "Christine Roeder and Tatsiana Kupreichyk and Lothar Gremer and Schaefer, {Luisa U.} and Pothula, {Karunakar R.} and Ravelli, {Raimond B. G.} and Dieter Willbold and Wolfgang Hoyer and Schroeder, {Gunnar F.}",

year = "2020",

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doi = "10.1038/s41594-020-0442-4",

language = "English",

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TY - JOUR

T1 - Cryo-EM structure of islet amyloid polypeptide fibrils reveals similarities with amyloid-β fibrils

AU - Roeder, Christine

AU - Kupreichyk, Tatsiana

AU - Gremer, Lothar

AU - Schaefer, Luisa U.

AU - Pothula, Karunakar R.

AU - Ravelli, Raimond B. G.

AU - Willbold, Dieter

AU - Hoyer, Wolfgang

AU - Schroeder, Gunnar F.

PY - 2020/7

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N2 - 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-angstrom 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-beta (A beta) fibrils, which might account for the epidemiological link between T2D and AD and reports on IAPP-A beta cross-seeding in vivo. The results structurally link the early-onset T2D IAPP genetic polymorphism (encoding Ser20Gly) with the AD Arctic mutation (Glu22Gly) of A beta and support the design of inhibitors and imaging probes for IAPP fibrils.Cryo-EM analyses of amyloid fibrils formed by synthetic human IAPP show an S-fold for the main polymorph, with the backbone superimposable with those of amyloid-beta fibrils in antiparallel arrangement.

AB - 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-angstrom 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-beta (A beta) fibrils, which might account for the epidemiological link between T2D and AD and reports on IAPP-A beta cross-seeding in vivo. The results structurally link the early-onset T2D IAPP genetic polymorphism (encoding Ser20Gly) with the AD Arctic mutation (Glu22Gly) of A beta and support the design of inhibitors and imaging probes for IAPP fibrils.Cryo-EM analyses of amyloid fibrils formed by synthetic human IAPP show an S-fold for the main polymorph, with the backbone superimposable with those of amyloid-beta fibrils in antiparallel arrangement.

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