Analysis of Proline Substitutions Reveals the Plasticity and Sequence Sensitivity of Human IAPP Amyloidogenicity and Toxicity
| Autor: | Aisha Ben-Younis, Konstantinos Thalassinos, Charles Eldrid, Daniel P. Raleigh, Zachary Ridgway, Daeun Noh, Alexander Zhyvoloup |
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| Rok vydání: | 2020 |
| Předmět: |
endocrine system
Amyloid Aging Biochemistry & Molecular Biology Proline Dimer Context (language use) Neurodegenerative Medical Biochemistry and Metabolomics Alzheimer's Disease Biochemistry Article 03 medical and health sciences Residue (chemistry) chemistry.chemical_compound Medicinal and Biomolecular Chemistry Acquired Cognitive Impairment Humans Amino Acid Sequence Gene 0303 health sciences Chemistry 030302 biochemistry & molecular biology Diabetes Rational design Genetic Variation Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) In vitro Islet Amyloid Polypeptide Brain Disorders Amino Acid Substitution Dementia Generic health relevance Biochemistry and Cell Biology Algorithms |
| Zdroj: | Biochemistry, vol 59, iss 6 Biochemistry |
| Popis: | 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 IAPPA25PS29P 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. |
| Databáze: | OpenAIRE |
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