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Analysis of Baboon IAPP provides insight into amyloidogenicity and cytotoxicity of human IAPP

Analysis of Baboon IAPP provides insight into amyloidogenicity and cytotoxicity of human IAPP
Analysis of Baboon IAPP provides insight into amyloidogenicity and cytotoxicity of human IAPP
The polypeptide hormone islet amyloid polypeptide (IAPP) forms islet amyloid in type 2 diabetes, a process which contributes to pancreatic β-cell dysfunction and death. Not all species form islet amyloid, and the ability to do so correlates with the primary sequence. Humans form islet amyloid, but baboon IAPP has not been studied. The baboon peptide differs from human IAPP at three positions containing K1I, H18R, and A25T substitutions. The K1I substitution is a rare example of a replacement in the N-terminal region of amylin. The effect of this mutation on amyloid formation has not been studied, but it reduces the net charge, and amyloid prediction programs suggest that it should increase amyloidogenicity. The A25T replacement involves a nonconservative substitution in a region of IAPP that is believed to be important for aggregation, but the effects of this replacement have not been examined. The H18R point mutant has been previously shown to reduce aggregation in vitro. Baboon amylin forms amyloid on the same timescale as human amylin in vitro and exhibits similar toxicity toward cultured β-cells. The K1I replacement in human amylin slightly reduces toxicity, whereas the A25T substitution accelerates amyloid formation and enhances toxicity. Photochemical cross-linking reveals that the baboon amylin, like human amylin, forms low-order oligomers in the lag phase of amyloid formation. Ion-mobility mass spectrometry reveals broadly similar gas phase collisional cross sections for human and baboon amylin monomers and dimers, with some differences in the arrival time distributions. Preamyloid oligomers formed by baboon amylin, but not baboon amylin fibers, are toxic to cultured β-cells. The toxicity of baboon oligomers and lack of significantly detectable toxicity with exogenously added amyloid fibers is consistent with the hypothesis that preamyloid oligomers are the most toxic species produced during IAPP amyloid formation.
0006-3495
Ridgway, Zachary
54e178d9-753e-4e8a-8ba8-a139b15d85f0
Lee, Kyung-Hoon
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Zhyvoloup, Alexander
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Wong, Amy
883800a0-8af2-41a9-99a5-3e3db17e649f
Eldrid, Charles
caf78c85-1eae-4700-814a-01b5f0635a0b
Hannaberry, Eleni
5f04fc9f-1a77-4e9a-9f8c-b78c0b345ebe
Thalassinos, Konstantinos
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Abedini, Andidesh
08dc3f51-51c3-41ce-9f49-a341c010570c
Raleigh, Daniel P.
cb5a2e73-78ca-4321-90f5-5eeda8762a5a
Ridgway, Zachary
54e178d9-753e-4e8a-8ba8-a139b15d85f0
Lee, Kyung-Hoon
9de6b517-59fe-4720-befe-1393071e101a
Zhyvoloup, Alexander
5b0b4802-af34-4399-94e7-da217bda2538
Wong, Amy
883800a0-8af2-41a9-99a5-3e3db17e649f
Eldrid, Charles
caf78c85-1eae-4700-814a-01b5f0635a0b
Hannaberry, Eleni
5f04fc9f-1a77-4e9a-9f8c-b78c0b345ebe
Thalassinos, Konstantinos
75b3f786-6a27-420a-8727-97eafb34c022
Abedini, Andidesh
08dc3f51-51c3-41ce-9f49-a341c010570c
Raleigh, Daniel P.
cb5a2e73-78ca-4321-90f5-5eeda8762a5a

Ridgway, Zachary, Lee, Kyung-Hoon, Zhyvoloup, Alexander, Wong, Amy, Eldrid, Charles, Hannaberry, Eleni, Thalassinos, Konstantinos, Abedini, Andidesh and Raleigh, Daniel P. (2020) Analysis of Baboon IAPP provides insight into amyloidogenicity and cytotoxicity of human IAPP. Biophysical Journal, 118 (5). (doi:10.1016/j.bpj.2019.12.027).

Record type: Article

Abstract

The polypeptide hormone islet amyloid polypeptide (IAPP) forms islet amyloid in type 2 diabetes, a process which contributes to pancreatic β-cell dysfunction and death. Not all species form islet amyloid, and the ability to do so correlates with the primary sequence. Humans form islet amyloid, but baboon IAPP has not been studied. The baboon peptide differs from human IAPP at three positions containing K1I, H18R, and A25T substitutions. The K1I substitution is a rare example of a replacement in the N-terminal region of amylin. The effect of this mutation on amyloid formation has not been studied, but it reduces the net charge, and amyloid prediction programs suggest that it should increase amyloidogenicity. The A25T replacement involves a nonconservative substitution in a region of IAPP that is believed to be important for aggregation, but the effects of this replacement have not been examined. The H18R point mutant has been previously shown to reduce aggregation in vitro. Baboon amylin forms amyloid on the same timescale as human amylin in vitro and exhibits similar toxicity toward cultured β-cells. The K1I replacement in human amylin slightly reduces toxicity, whereas the A25T substitution accelerates amyloid formation and enhances toxicity. Photochemical cross-linking reveals that the baboon amylin, like human amylin, forms low-order oligomers in the lag phase of amyloid formation. Ion-mobility mass spectrometry reveals broadly similar gas phase collisional cross sections for human and baboon amylin monomers and dimers, with some differences in the arrival time distributions. Preamyloid oligomers formed by baboon amylin, but not baboon amylin fibers, are toxic to cultured β-cells. The toxicity of baboon oligomers and lack of significantly detectable toxicity with exogenously added amyloid fibers is consistent with the hypothesis that preamyloid oligomers are the most toxic species produced during IAPP amyloid formation.

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e-pub ahead of print date: 3 January 2020
Published date: 10 March 2020

Identifiers

Local EPrints ID: 446844
URI: http://eprints.soton.ac.uk/id/eprint/446844
ISSN: 0006-3495
PURE UUID: b16d9977-52e9-44c0-95eb-a915252f1259

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Date deposited: 24 Feb 2021 17:31
Last modified: 25 Nov 2021 19:39

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Contributors

Author: Zachary Ridgway
Author: Kyung-Hoon Lee
Author: Alexander Zhyvoloup
Author: Amy Wong
Author: Charles Eldrid
Author: Eleni Hannaberry
Author: Konstantinos Thalassinos
Author: Andidesh Abedini
Author: Daniel P. Raleigh

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