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

Research output: Contribution to journal › Article › Academic › peer-review

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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-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.

Original language	English
Pages (from-to)	660-667
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
Human amylin
Crystallography
Mechanism
System
S20g mutation
Gene
Dynamics
Atomic-resolution structure
Iapp
Alzheimers-disease

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10.1038/s41594-020-0442-4

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Cite this

@article{3ff42efb4efb4806977da2574aa9dced,

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-{\AA} 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{\textquoteright}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.",

keywords = "ATOMIC-RESOLUTION STRUCTURE, ALZHEIMERS-DISEASE, S20G MUTATION, HUMAN AMYLIN, DYNAMICS, IAPP, MECHANISM, SYSTEM, GENE, CRYSTALLOGRAPHY, Human amylin, Crystallography, Mechanism, System, S20g mutation, Gene, Dynamics, Atomic-resolution structure, Iapp, Alzheimers-disease",

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.}",

note = "Funding Information: We thank P.J. Peters and C. L{\'o}pez-Iglesias for advice and helpful discussions, H. Duimel for help with sample preparation and the M4I Division of Nanoscopy of Maastricht University for microscope access and support. The authors gratefully acknowledge the computing time granted by the J{\"u}lich Aachen Research Alliance High-Performance Computing (JARA-HPC) Vergabegremium and VSR commission on the supercomputer JURECA at Forschungszentrum J{\"u}lich. We acknowledge support from a European Research Council (ERC) Consolidator grant (no. 726368; W.H.), the Alzheimer Forschung Initiative e.V. and Alzheimer Nederland (project no. 19082CB; R.B.G.R. and G.F.S.), the Russian Science Foundation (RSF; project no. 20-64-46027; L.G. and D.W.) and the Helmholtz Association Initiative and Networking Fund (project no. ZT-I-0003; K.R.P. and G.F.S.). Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2020",

month = jul,

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

language = "English",

volume = "27",

pages = "660--667",

journal = "Nature Structural and Molecular Biology",

issn = "1545-9993",

publisher = "Nature Publishing Group",

number = "7",

}

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.

N1 - Funding Information: We thank P.J. Peters and C. López-Iglesias for advice and helpful discussions, H. Duimel for help with sample preparation and the M4I Division of Nanoscopy of Maastricht University for microscope access and support. The authors gratefully acknowledge the computing time granted by the Jülich Aachen Research Alliance High-Performance Computing (JARA-HPC) Vergabegremium and VSR commission on the supercomputer JURECA at Forschungszentrum Jülich. We acknowledge support from a European Research Council (ERC) Consolidator grant (no. 726368; W.H.), the Alzheimer Forschung Initiative e.V. and Alzheimer Nederland (project no. 19082CB; R.B.G.R. and G.F.S.), the Russian Science Foundation (RSF; project no. 20-64-46027; L.G. and D.W.) and the Helmholtz Association Initiative and Networking Fund (project no. ZT-I-0003; K.R.P. and G.F.S.). Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

PY - 2020/7

Y1 - 2020/7

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-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.

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-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.

KW - ATOMIC-RESOLUTION STRUCTURE

KW - ALZHEIMERS-DISEASE

KW - S20G MUTATION

KW - HUMAN AMYLIN

KW - DYNAMICS

KW - IAPP

KW - MECHANISM

KW - SYSTEM

KW - GENE

KW - CRYSTALLOGRAPHY

KW - Human amylin

KW - Crystallography

KW - Mechanism

KW - System

KW - S20g mutation

KW - Gene

KW - Dynamics

KW - Atomic-resolution structure

KW - Iapp

KW - Alzheimers-disease

U2 - 10.1038/s41594-020-0442-4

DO - 10.1038/s41594-020-0442-4

M3 - Article

C2 - 32541895

SN - 1545-9993

VL - 27

SP - 660

EP - 667

JO - Nature Structural and Molecular Biology

JF - Nature Structural and Molecular Biology

IS - 7

ER -