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Analysis of proline substitutions reveals the plasticity and sequence sensitivity of human IAPP amyloidogenicity and toxicity

Analysis of proline substitutions reveals the plasticity and sequence sensitivity of human IAPP amyloidogenicity and toxicity
Analysis of proline substitutions reveals the plasticity and sequence sensitivity of human IAPP amyloidogenicity and toxicity
Pancreatic amyloid formation by the polypeptide IAPP contributes to β-cell dysfunction in type 2 diabetes. There is a 1:1 correspondence between the ability of IAPP from different species to form amyloid in vitro and the susceptibility of the organism to develop diabetes. Rat IAPP is non-amyloidogenic and differs from human IAPP at six positions, including three proline replacements: A25P, S28P, and S29P. Incorporation of these proline residues into human IAPP leads to a non-amyloidogenic analogue that is used clinically. The role of the individual proline residues is not understood. We examine the three single and three double proline substitutions in the context of human IAPP. An S28P substitution significantly decreases amyloidogenicity and toxicity, while an S29P substitution has very modest effects despite being an identical replacement just one residue away. The consequences of the A25P substitution are between those of the two Ser to Pro substitutions. Double analogues containing an S28P replacement are less amyloidogenic and less toxic than the IAPPA25P S29P double analogue. Ion mobility mass spectrometry reveals that there is no correlation between the monomer or dimer conformation as reported by collision cross section measurements and the time to form amyloid. The work reveals both the plasticity of IAPP amyloid formation and the exquisite sequence sensitivity of IAPP amyloidogenicity and toxicity. The study highlights the key role of the S28P substitution and provides information that will aid in the rational design of soluble variants of IAPP. The variants studied here offer a system for further exploring features that control IAPP toxicity.
0006-2960
742-754
Ridgway, Zachary
54e178d9-753e-4e8a-8ba8-a139b15d85f0
Eldrid, Charles
caf78c85-1eae-4700-814a-01b5f0635a0b
Zhyvoloup, Alexander
5b0b4802-af34-4399-94e7-da217bda2538
Ben-Younis, Aisha
b29329e8-bc8b-4f17-92c4-fc16365cc1e7
Noh, Daeun
d53941ef-5175-4718-a306-c32b4e70d6c6
Thalassinos, Konstantinos
75b3f786-6a27-420a-8727-97eafb34c022
Raleigh, Daniel P.
cb5a2e73-78ca-4321-90f5-5eeda8762a5a
Ridgway, Zachary
54e178d9-753e-4e8a-8ba8-a139b15d85f0
Eldrid, Charles
caf78c85-1eae-4700-814a-01b5f0635a0b
Zhyvoloup, Alexander
5b0b4802-af34-4399-94e7-da217bda2538
Ben-Younis, Aisha
b29329e8-bc8b-4f17-92c4-fc16365cc1e7
Noh, Daeun
d53941ef-5175-4718-a306-c32b4e70d6c6
Thalassinos, Konstantinos
75b3f786-6a27-420a-8727-97eafb34c022
Raleigh, Daniel P.
cb5a2e73-78ca-4321-90f5-5eeda8762a5a

Ridgway, Zachary, Eldrid, Charles, Zhyvoloup, Alexander, Ben-Younis, Aisha, Noh, Daeun, Thalassinos, Konstantinos and Raleigh, Daniel P. (2020) Analysis of proline substitutions reveals the plasticity and sequence sensitivity of human IAPP amyloidogenicity and toxicity. Biochemistry, 59 (6), 742-754. (doi:10.1021/acs.biochem.9b01109).

Record type: Article

Abstract

Pancreatic amyloid formation by the polypeptide IAPP contributes to β-cell dysfunction in type 2 diabetes. There is a 1:1 correspondence between the ability of IAPP from different species to form amyloid in vitro and the susceptibility of the organism to develop diabetes. Rat IAPP is non-amyloidogenic and differs from human IAPP at six positions, including three proline replacements: A25P, S28P, and S29P. Incorporation of these proline residues into human IAPP leads to a non-amyloidogenic analogue that is used clinically. The role of the individual proline residues is not understood. We examine the three single and three double proline substitutions in the context of human IAPP. An S28P substitution significantly decreases amyloidogenicity and toxicity, while an S29P substitution has very modest effects despite being an identical replacement just one residue away. The consequences of the A25P substitution are between those of the two Ser to Pro substitutions. Double analogues containing an S28P replacement are less amyloidogenic and less toxic than the IAPPA25P S29P double analogue. Ion mobility mass spectrometry reveals that there is no correlation between the monomer or dimer conformation as reported by collision cross section measurements and the time to form amyloid. The work reveals both the plasticity of IAPP amyloid formation and the exquisite sequence sensitivity of IAPP amyloidogenicity and toxicity. The study highlights the key role of the S28P substitution and provides information that will aid in the rational design of soluble variants of IAPP. The variants studied here offer a system for further exploring features that control IAPP toxicity.

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e-pub ahead of print date: 10 January 2020
Published date: 18 February 2020

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Local EPrints ID: 446849
URI: http://eprints.soton.ac.uk/id/eprint/446849
ISSN: 0006-2960
PURE UUID: 6a2b79a8-3d06-4d11-a764-1841bb86c974

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Date deposited: 24 Feb 2021 17:31
Last modified: 25 Nov 2021 20:38

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Contributors

Author: Zachary Ridgway
Author: Charles Eldrid
Author: Alexander Zhyvoloup
Author: Aisha Ben-Younis
Author: Daeun Noh
Author: Konstantinos Thalassinos
Author: Daniel P. Raleigh

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