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Analysis of Proline Substitutions Reveals the Plasticity and Sequence Sensitivity of Human IAPP Amyloidogenicity and Toxicity

Ridgway, Z; Eldrid, CFS; Zhyvoloup, A; Ben-Younis, A; Noh, D; Thalassinos, K; Raleigh, DP; (2020) Analysis of Proline Substitutions Reveals the Plasticity and Sequence Sensitivity of Human IAPP Amyloidogenicity and Toxicity. Biochemistry , 59 (6) pp. 742-754. 10.1021/acs.biochem.9b01109. Green open access

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Abstract

Pancreatic amyloid formation by the polypeptide IAPP contributes to -cell dysfunction in type 2 diabetes. There is a one-to-one 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, S29P. Incorporation of these proline residues into human IAPP leads to a non-amyloidogenic analogue which 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 mutants containing an S28P replacement are less amyloidogenic and less toxic than the IAPPA25P S29P double mutant. Ion mobility mass spectrometry reveals that there is no correlation between monomer or dimer conformation as reported by collision cross sections 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 the rational design of soluble variants of IAPP. The variants studied here offer a system to further explore features which control IAPP toxicity.

Type: Article
Title: Analysis of Proline Substitutions Reveals the Plasticity and Sequence Sensitivity of Human IAPP Amyloidogenicity and Toxicity
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acs.biochem.9b01109
Publisher version: https://doi.org/10.1021/acs.biochem.9b01109
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Nanofibers, Peptides and proteins ,Monomers, Assays, Toxicity
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
URI: https://discovery.ucl.ac.uk/id/eprint/10089740
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