| Autor: |
Johanna Kliche, Leandro Simonetti, Izabella Krystkowiak, Hanna Kuss, Marcel Diallo, Emma Rask, Jakob Nilsson, Norman E Davey, Ylva Ivarsson |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
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| Zdroj: |
Molecular Systems Biology, Vol 20, Iss 9, Pp 1025-1048 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
1744-4292 |
| DOI: |
10.1038/s44320-024-00055-4 |
| Popis: |
Abstract Whole genome and exome sequencing are reporting on hundreds of thousands of missense mutations. Taking a pan-disease approach, we explored how mutations in intrinsically disordered regions (IDRs) break or generate protein interactions mediated by short linear motifs. We created a peptide-phage display library tiling ~57,000 peptides from the IDRs of the human proteome overlapping 12,301 single nucleotide variants associated with diverse phenotypes including cancer, metabolic diseases and neurological diseases. By screening 80 human proteins, we identified 366 mutation-modulated interactions, with half of the mutations diminishing binding, and half enhancing binding or creating novel interaction interfaces. The effects of the mutations were confirmed by affinity measurements. In cellular assays, the effects of motif-disruptive mutations were validated, including loss of a nuclear localisation signal in the cell division control protein CDC45 by a mutation associated with Meier-Gorlin syndrome. The study provides insights into how disease-associated mutations may perturb and rewire the motif-based interactome. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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