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| Status |
Public on Aug 02, 2024 |
| Title |
Amyloids “at the border”: deep mutagenesis and random sequence extension reveal an incomplete amyloid-forming motif in Bri2 that turns amyloidogenic upon C-terminal extension |
| Organism |
Saccharomyces cerevisiae |
| Experiment type |
Other
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| Summary |
Stop-loss mutations cause over twenty different diseases. The effects of stop-loss mutations can have multiple consequences that are, however, hard to predict. Stop-loss in ITM2B/BRI2 results in C-terminal extension of the encoded protein and, upon furin cleavage, in the production of two 34 amino acid long peptides, ADan and ABri, that accumulate as amyloids in the brains of patients affected by familial Danish and British Dementia. To systematically explore the consequences of Bri2 C-terminal extension, here, we measure amyloid formation for 676 ADan substitutions and identify the region that forms the putative amyloid core of ADan fibrils, located between positions 20 and 26, where stop-loss occurs. Moreover, we measure amyloid formation for ~18,000 random C-terminal extensions of Bri2 and find that ~32% of these sequences can nucleate amyloids. We find that the amino acid composition of these nucleating sequences varies with peptide length and that short extensions of 2 specific amino acids (Aliphatics, Aromatics and Cysteines) are sufficient to generate novel amyloid cores. Overall, our results show that the C-terminus of Bri2 contains an incomplete amyloid motif that can turn amyloidogenic upon extension. C-terminal extension with de novo formation of amyloid motifs may thus be a widespread pathogenic mechanism resulting from stop-loss, highlighting the importance of determining the impact of these mutations for other sequences across the genome.
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| Overall design |
Systematic measurement of the nucleation of Bri2 random extension of 12 amino acids (NNK degenerate codons).
Three independent experiments performed. Illumina sequencing of 1 input sample and 3 output samples (after selection for amyloid nucleation) per experiment.
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| Contributor(s) |
Martín M, Bolognesi B |
| Citation missing |
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| Submission date |
Jun 25, 2024 |
| Last update date |
Aug 02, 2024 |
| Contact name |
Mariano Martín |
| E-mail(s) |
mmartin@ibecbarcelona.eu
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| Organization name |
IBEC
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| Street address |
c/ Baldiri Reixac 10-12
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| City |
Barcelona |
| ZIP/Postal code |
08028 |
| Country |
Spain |
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| Platforms (1) |
| GPL31112 |
NextSeq 2000 (Saccharomyces cerevisiae) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA1128177 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE270792_MM_BB_processed_data_240526.xlsx |
872.7 Kb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
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