Abstract
Amyloid fibrils formed by the islet amyloid polypeptide cause pancreatic beta-cell damage, resulting in reduced insulin secretion and type 2 diabetes. Changes in the amino acid sequence of this peptide can influence its aggregation rate, and animals expressing variants that do not form amyloids do not develop type 2 diabetes. Conversely, specific single amino acid changes can accelerate the aggregation rate of this peptide. Here, we employ deep mutational scanning to measure the ability of 1916 islet amyloid polypeptide variants, including substitutions, insertions, truncations and deletions, to nucleate amyloids. Our results identify a continuous stretch of residues from 15 to 32 that is particularly sensitive to mutation. This region, which is likely structured in amyloids, matches the core of the early aggregated species formed by this peptide in vitro. Within this region, mutations in residues 21 to 27 have a substantial effect, suggesting tighter structural constraints. Finally, we compare the mutational atlas of the islet amyloid polypeptide to that of amyloid beta - the peptide that aggregates in Alzheimer’s disease - and find that mutations that slow down nucleation correlate between the two amyloids, but mutations that accelerate nucleation in one amyloid cannot be used to predict mutational effects in the other.
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Data availability
Raw sequencing data are deposited in the European Nucleotide Archive (ENA) under project accession number: PRJEB104038. The processed data (nucleation score estimates and associated error terms) are provided in Supplementary Data 2 and have also been deposited in MaveDB84, a dedicated repository for standardized deep mutational scanning data. The processed dataset can be found by searching IAPP from the MaveDB landing page [https://www.mavedb.org/]. The Universal Resource Name (URN) for the dataset is urn:mavedb:00001253-a [https://www.mavedb.org/experiments/urn:mavedb:00001253-a]. The amyloid beta 42 nucleation dataset was obtained from Zenodo [https://doi.org/10.5281/zenodo.7255570]. The coordinates for the PDB structures used in the study were obtained with accession numbers 7M6121, 7M6221, 7M6421, 7M6521, 6Y1A14, 6ZRF23, 8R4I19, 6VW220, 8AWT22, 8AZ022, 8AZ122, 8AZ222, 8AZ322, 8AZ422, 8AZ522, 8AZ622, 8AZ722, 6ZRR23, 6ZRQ23, 7Q4M24. Variant frequency data were obtained from gnomAD v4.1.069 [https://gnomad.broadinstitute.org/gene/ENSG00000121351?dataset=gnomad_r4] and UK Biobank [https://www.ukbiobank.ac.uk/enable-your-research/register]. Source data are provided with this paper.
Code availability
All analysis scripts are available in the project’s GitHub repository [https://github.com/BEBlab/MAVE-IAPP] and in Zenodo [https://doi.org/10.5281/zenodo.18509746].
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Acknowledgements
M.B. was supported by the fellowship “Ayudas para contratos predoctorales para la formación de doctores 2019” (PRE2019-088300) from the Spanish Ministry of Science, Innovation and Universities. The project that gave rise to these results has received funding from “la Caixa” Research Foundation under the grant agreement LCF/PR/HR21/52410004 (project ‘DeepAmyloids’). Work in the lab of B.B. is also supported by the Spanish Ministry of Science, Innovation and Universities (PID2021-127761OB-I00 and RYC2020-028861-I, funded by MCIN/AEI/10.13039/501100011033, “ERDF A way of making Europe” and “ESF Investing in your future”), and by the European Union (ERC Consolidator, Glam-MAP, 101125484). Views and opinions expressed are, however, those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council. Neither the European Union nor the granting authority can be held responsible for them. IBEC is a member of the CERCA Program/Generalitat de Catalunya. We thank the Chernoff and the Lehner lab for providing strains and plasmids, and the CRG Genomics core technology for sequencing. We thank Prof. John Perry, Dr. Yajie Zhao, Prof. Ben Lehner, Carla Folgado, and the B.B. lab members for discussing our data.
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B.B. conceptualized and supervised the project. C.B. and M.B. designed the libraries and performed the experiments. M.B. analyzed the data and conducted the UK Biobank analyses. B.B. and M.B. interpreted the results and wrote the manuscript. All authors reviewed and edited the manuscript.
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Badia, M., Batlle, C. & Bolognesi, B. Massively parallel quantification of mutational impact on IAPP amyloid formation. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70611-z
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DOI: https://doi.org/10.1038/s41467-026-70611-z
