Systematic discovery of protein interaction interfaces using AlphaFold and experimental validation
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Published:2024-01-15
Issue:2
Volume:20
Page:75-97
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ISSN:1744-4292
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Container-title:Molecular Systems Biology
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language:en
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Short-container-title:Mol Syst Biol
Author:
Lee Chop YanORCID, Hubrich DalmiraORCID, Varga Julia KORCID, Schäfer ChristianORCID, Welzel Mareen, Schumbera Eric, Djokic Milena, Strom Joelle MORCID, Schönfeld JonasORCID, Geist Johanna L, Polat Feyza, Gibson Toby JORCID, Keller Valsecchi Claudia Isabelle, Kumar Manjeet, Schueler-Furman OraORCID, Luck KatjaORCID
Abstract
AbstractStructural resolution of protein interactions enables mechanistic and functional studies as well as interpretation of disease variants. However, structural data is still missing for most protein interactions because we lack computational and experimental tools at scale. This is particularly true for interactions mediated by short linear motifs occurring in disordered regions of proteins. We find that AlphaFold-Multimer predicts with high sensitivity but limited specificity structures of domain-motif interactions when using small protein fragments as input. Sensitivity decreased substantially when using long protein fragments or full length proteins. We delineated a protein fragmentation strategy particularly suited for the prediction of domain-motif interfaces and applied it to interactions between human proteins associated with neurodevelopmental disorders. This enabled the prediction of highly confident and likely disease-related novel interfaces, which we further experimentally corroborated for FBXO23-STX1B, STX1B-VAMP2, ESRRG-PSMC5, PEX3-PEX19, PEX3-PEX16, and SNRPB-GIGYF1 providing novel molecular insights for diverse biological processes. Our work highlights exciting perspectives, but also reveals clear limitations and the need for future developments to maximize the power of Alphafold-Multimer for interface predictions.
Funder
German Research Foundation European Union Horizon 2020 UBIMOTIF programme Israel Science Foundation IMB collaborative research PhD stipend Ministry of Science and Health (MWG), Rhineland Palatinate
Publisher
Springer Science and Business Media LLC
Subject
Applied Mathematics,Computational Theory and Mathematics,General Agricultural and Biological Sciences,General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Information Systems
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